Template-fixed beta-hairpin peptidomimetics with cxcr4 antagonizing activity

ABSTRACT

Template-fixed β-hairpin peptidomimetics of the general formula (I) 
     
       
         
         
             
             
         
       
     
     wherein Z is a template-fixed chain of 12, 14 or 18 α-amino acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid), are Gly, NMeGly, Pro or Pip, or of certain types which, as the remaining symbols in the above formula, are defined in the description and the claims, and salts thereof, have CXCR4 antagonizing properties These β-hairpin peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation application of U.S.application Ser. No. 12/828,998 which is a divisional application ofU.S. application Ser. No. 10/555,088, issued as U.S. Pat. No. 7,786,078filed on Oct. 31, 2005 and afforded a §371 date of Dec. 16, 2005, whichU.S. application Ser. No. 10/555,088 is the National Stage filing in theU.S. of International Application No. PCT/EP2004/004535, filed Apr. 29,2004, which claims priority to PCT/EP03/04640, filed May 2, 2003, theentire contents of all which are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention provides template-fixed βhairpin peptidomimeticsincorporating template-fixed chains of 12, 14 or 18 α-amino acidresidues which, depending on their positions in the chains, are Gly,NMeGly, Pro or Pip, or of certain types, as defined hereinbelow. Thesetemplate-fixed β-hairpin mimetics have CXCR4 antagonizing activity. Inaddition, the present invention provides an efficient synthetic processby which these compounds can, if desired, be made in parallellibrary-format. These β-hairpin peptidomimetics show improved efficacy,bioavailability, half-life and most importantly a significantly enhancedratio between CXCR4 antagonizing activity on the one hand, and hemolysison red blood cells and cytotoxicity on the other.

BACKGROUND OF THE INVENTION

To date the available therapies for the treatment of HIV infections havebeen leading to a remarkable improvement in symptoms and recovery fromdisease in infected people. Although the highly active anti retroviraltherapy (HAART-therapy) which involves a combination of reversetranscriptase/protease inhibitor has dramatically improved the clinicaltreatment of individuals with AIDS or HIV infection there have stillremained several serious problems including multi drug resistance,significant adverse effects and high costs. Particularly desired areanti HIV agents that block the HIV infection at an early stage of theinfection, such as the viral entry.

It has recently been recognized that for efficient entry into targetcells, human immunodeficiency viruses require the chemokine receptorsCCR5 and CXCR4 as well as the primary receptor CD4 (N. Levy, Engl. J.Med., 335, 29, 1528-1530). Accordingly, an agent which could block theCXCR4 chemokine receptors should prevent infections in healthyindividuals and slow or halt viral progression in infected patients(Science, 1997, 275, 1261-1264).

Among the different types of CXCR4 inhibitors (M. Schwarz, T. N. C.Wells, A. E. I. Proudfoot, Receptors and Channels, 2001, 7, 417-428),one emerging class is based on naturally occurring cationic peptideanalogues derived from Polyphemusin II which have an antiparallel3-sheet structure, and a β-hairpin that is maintained by two disulfidebridges (H. Nakashima, M. Masuda, T. Murakami, Y. Koyanagi, A.Matsumoto, N. Fujii, N. Yamamoto, Antimicrobial Agents and Chemoth.1992, 36, 1249-1255; H. Tamamura, M. Kuroda, M. Masuda, A. Otaka, S.Funakoshi, H. Nakashima, N. Yamamoto, M. Waki, A. Matsumotu, J. M.Lancelin, D. Kohda, S. Tate, F. Inagaki, N. Fujii, Biochim. Biophys.Acta 1993, 209, 1163; WO 95/10534 A1).

Synthesis of structural analogs and structural studies by nuclearmagnetic resonance (NMR) spectroscopy have shown that the cationicpeptides adopt well defined β-hairpins conformations, due to theconstraining effect of the one or two disulfide bridges (H. Tamamura, M.Sugioka, Y. Odagaki, A. Omagari, Y. Kahn, S. Oishi, H. Nakashima, N.Yamamoto, S. C. Peiper, N. Hamanaka, A. Otaka, N. Fujii, Bioorg. Med.Chem. Lett. 2001, 359-362). These results show that the β-hairpinstructure plays an important role in CXCR4 antagonizing activity.

Additional structural studies have also indicated that the antagonizingactivity can also be influenced by modulating amphiphilic structure andthe pharmacophore (H. Tamamura, A. Omagari, K. Hiramatsu, K. Gotoh, T.Kanamoto, Y. Xu, E. Kodama, M. Matsuoka, T. Hattori, N. Yamamoto, H.Nakashima, A. Otaka, N. Fujii, Bioorg. Med. Chem. Lett. 2001, 11,1897-1902; H. Tamamura, A. Omagari, K. Hiramatsu, S. Oishi, H.Habashita, T. Kanamoto, K. Gotoh, N. Yamamoto, H. Nakashima, A. Otaka N.Fujii, Bioorg. Med. Chem. 2002, 10, 1417-1426; H. Tamamura, K.Hiramatsu, K. Miyamoto, A. Omagari, S. Oishi, H. Nakashima, N. Yamamoto,Y. Kuroda, T. Nakagawa, A. Otaki, N. Fujii, Bioorg. Med. Chem. Letters2002, 12, 923-928).

A key issue in the design of CXCR4 antagonizing peptides is selectivity.The polyphemusin II derived analogs exert still a cytotoxicity despiteimprovements (K. Matsuzaki, M. Fukui, N. Fujii, K. Miyajima, Biochim.Biophys. Acta 1991, 259, 1070; A. Otaka, H. Tamamura, Y. Terakawa, M.Masuda, T. Koide, T. Murakami, H. Nakashima, K. Matsuzaki, K. Miyajima,T. Ibuka, M. Waki, A. Matsumoto, N. Yamamoto, N. Fujii Biol. Pharm.Bull. 1994, 17, 1669 and cited references above).

This cytotoxic activity essentially obviates its use in vivo, andrepresents a serious disadvantage in clinical applications. Beforeintravenous use can be considered, the general toxicity, protein-bindingactivity in blood serum, as well as protease stability become seriousissues which must be adequately addressed.

Recently, it has been shown that the CXCR4-receptor is not only involvedin the entry of HIV but also in the chemotactic activity of cancercells, such as breast cancer metastasis or in metastasis of ovariancancer (A. Muller, B. Homey, H. Soto, N. Ge, D. Catron, M. E. Buchanan,T. Mc Clanahan, E. Murphey, W. Yuan, S. N. Wagner, J. Luis Barrera, A.Mohar, E. Verastegui, A. Zlotnik, Nature 2001, 50, 410, J. M. Hall, K.S. Korach, Molecular Endocrinology, 2003, 1-47), Non-Hodgin's Lymphoma(F. Bertolini, C. DellAgnola, P. Manusco, C. Rabascio, A. Burlini, S.Monestiroli, A. Gobbi, G. Pruneri, G. Martinelli, Cancer Research 2002,62, 3106-3112), or lung cancer (T. Kijima, G. Maulik, P. C. Ma, E. V.Tibaldi, R: E. Turner, B. Rollins, M. Sattler, B. E. Johnson, R. Salgia,Cancer Research 2002, 62, 6304-6311), melanoma, prostate cancer, kidneycancer, neuroblastomia, pancreatic cancer, multiple myeloma, chroniclymphocytic leukemia (H. Tamamura et al. Febs Letters 2003, 550 79-83,cited ref.) Blocking the chemotactic activity with a CXCR4 inhibitorshould stop the migration of cancer cells.

The CXCR4 receptor has also been implicated in the growth andproliferation of tumors. It was shown that activation of the CXCR4receptor was critical for the growth of both malignant neuronal andglial tumors, and small cell lung tumors. Moreover, systemicadministration of the CXCR4 antagonist AMD3100 inhibits growth ofintracranial glioblastoma and medulloblastoma xenografts by increasingapoptosis and decreasing the proliferation of tumor cells (Rubin J B,Kung A L, Klein R S, Chan J A, Sun Y, Schmidt K, Kieran M W, Luster A D,Segal R A. Proc Natl Acad Sci USA. 2003 100(23):13513-13518, Barbero S,Bonavia R, Bajetto A, Porcile C, Pirani P, Ravetti J L, Zona C L,Spaziante R, Florio T, Schettini G. Stromal Cancer Res. 2003,63(8):1969-1974, Kijima T, Maulik G, Ma P C, Tibaldi E V, Turner R E,Rollins B, Sattler M, Johnson B E, Salgia R. Cancer Res. 2002;62(21):6304-631 1, Cancer Res. 2002; 62(11):3106-3112.

The chemokine stromal cell-derived factor-1 (CXCL12/SDF-1) and itsreceptor CXCR4 are involved in trafficking of B cells and hematopoieticprogenitors. It has been shown that the CXCR4 receptor plays animportant role in the release of stem cells from the bone marrow to theperipheral blood. The receptor is for instance expressed on CD34+ cells,and has been implicated in the process of CD34+ cell migration andhoming. This activity of the CXCR4 receptor could be very important forefficient apheresis collections of peripheral blood stem cell.Autologous peripheral blood cells provide a rapid and sustainedhematopoietic recovery following autotransplantation after theadministration of high-dose chemotherapy or radiotherapy in patientswith haematological malignancies and solid tumors. (W C. Liles et al,Blood 2003, 102, 2728-2730).

There is increasing evidence that suggests that chemokines in generaland the interaction between the chemoattractant CXCL12/stromalcell-derived factor-I alpha and its receptor CXCR4 in particular play apivotal role in angiogenesis. Chemokines induce angiogenesis directly bybinding their cognate receptors on endothelial cells or indirectly bypromoting inflammatory cell infiltrates, which deliver other angiogenicstimuli. A number of proinflammatory chemokines including interleukin 8(IL-8), growth-regulated oncogene, stromal cell-derived factor 1(SDF-1), monocyte chemotactic protein 1 (MCP-1), eotaxin 1, and I-309have been shown to act as direct inducers of angiogenesis. (Chen X,Beutler J A, McCloud T G, Loehfelm A, Yang L, Dong H F, Chertov O Y,Salcedo R, Oppenheim J J, Howard O M. Clin Cancer Res. 20039(8):3115-3123, Salcedo R, Oppenheim J J. Microcirculation 2003(3-4):359-370)

It is well established that chemokines are involved in a number ofinflammatory pathologies and some of them show a pivotal role in themodulation of osteoclast development. Immunostaining for SDF-1 (CXCL12)on synovial and bone tissue biopsies from both rheumatoid arthritis (RA)and osteoarthritis (OA) samples have revealed strong increases in theexpression levels under inflammatory conditions. (Grassi F, Cristino S,Toneguzzi S, Piacentini A, Facchini A, Lisignoli G. J Cell Physiol.2004; 199(2):244-251. It seems likely that the CXCR4 receptor plays animportant role in inflammatory diseases e.g. such as rheumatoidarthritis, asthma, or multiple sclerose (K. R. Shadidi et al,Scandinavian Journal of Immunology, 2003, 57, 192-198, J. A. Gonzalo JImmunol. 2000, 165, 499-508, S. Hatse et al, FEBS Letters 2002 527,255-262 and cited references).

The mediation of recruitment of immune cells to sites of inflammationshould be stopped by a CXCR4 inhibitor.

In the compounds described below, a new strategy is introduced tostabilize beta-hairpin conformations in cyclic backbone-turnpeptidomimetics exhibiting high CXCR4 antagonizing activity, beinguseful for efficient apheresis collections of peripheral blood stemcells, and having anticancer activity and anti inflammatory activity.

This involves transplanting the cationic and hydrophobic hairpinsequence onto a template, whose function is to restrain the peptide loopbackbone into a hairpin geometry. The rigidity of the hairpin may befurther influenced by introducing a disulfide bridge. Template-boundhairpin mimetic peptides have been described in the literature (D,Obrecht, M. Altorfer, J. A. Robinson, Adv. Med. Chem. 1999, 4, 1-68; J.A. Robinson, Syn. Lett. 2000, 4, 429-441), but such molecules have notpreviously been evaluated for development of CXCR4 antagonizingpeptides. However, the ability to generate β-hairpin peptidomimeticsusing combinatorial and parallel synthesis methods has now beenestablished (L. Jiang, K. Moehle, B. Dhanapal, D. Obrecht, J. A.Robinson, Helv. Chim. Acta. 2000, 83, 3097-3112).

These methods allow the synthesis and screening of large hairpin mimeticlibraries, which in turn considerably facilitates structure-activitystudies, and hence the discovery of new molecules with highly potentCXCR4 antagonizing activity or anti cancer activity or anti inflammatoryactivity and low hemolytic activity to human red blood cells. β-Hairpinpeptidomimetics obtained by the approach described here are useful asAnti-HIV agents, anticancer agents, as inhibitors of tumor growth or asapoptosis inducing agents, anti-metastasis agents, and anti inflammatoryagents or as agents that can be used in apheresis collections ofperipheral blood stem cells. The β-hairpin peptidomimetics can be usedfor preventing HIV infections in healthy individuals or for slowing andhalting viral progression in infected patients; or where cancer ismediated or resulting from CXCR4 receptor activity; or whereimmunological diseases are mediated or resulting from CXCR4 receptoractivity; or for treating immunosuppression; or during apheresiscollections of peripheral blood stem cells. The β-hairpinpeptidomimetics can be used for preventing HIV infections in healthyindividuals or for slowing and halting viral progression in infectedpatients; or where cancer is mediated or resulting from CXCR4 receptoractivity; or where immunological diseases are mediated or resulting fromCXCR4 receptor activity; or for treating immunosuppression; or duringapheresis collections of peripheral blood stem cells.

SUMMARY OF THE INVENTION

The β-hairpin peptidomimetics of the present invention are compounds ofthe general formula

is a group of one of the formulae

is Gly or the residue of an L-α-amino acid with B being a residue offormula —NR²⁰CH(R⁷¹)— or the enantiomer of one of the groups A1 to A69as defined hereinafter;

is a group of one of the formulae

-   -   R¹ is H; lower alkyl; or aryl-lower alkyl;    -   R² is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R³ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵—;        —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁵ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁶ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁷ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(r)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁸ is H; Cl; F; CF₃; NO₂; lower alkyl; lower alkenyl; aryl;        aryl-lower alkyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹),        NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)COR⁶⁴;    -   R⁹ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(C₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R¹⁰ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;        —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;        —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or        —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R¹¹ is H—; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹, —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰ ₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R¹² is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(r)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R¹³ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(q)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁴;        —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(q)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R¹⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(o)CONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(q)(CHR⁶¹)_(s)SOR²; or —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R¹⁵ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁶ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R¹⁷ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)OR⁵⁵;        —(CH₂)_(q)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(q)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R¹⁸ is alkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)₅PO(OR⁶⁰)₂;        —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R¹⁹ is lower alkyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; or    -   R¹⁸ and R¹⁹ taken together can form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;    -   R²⁰ is H; alkyl; alkenyl; or aryl-lower alkyl;    -   R²¹ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R²² is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R²⁴ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(o)CONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R²⁴ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸SR⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R²⁵ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R²⁶ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)SOR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(r)NR³³R³⁴;        —(CH₂)_(m)(CHR⁶¹)_(s)OCoNR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; or    -   R²⁵ and R²⁶ taken together can form: —(CH₂)₂₋₆—;        —(CH₂)_(r)O(CH₂)_(r)—; —(CH₂)_(r)S(CH₂)_(r)—; or        —(CH₂)_(r)NR⁵⁷(CH₂)_(r)—;    -   R²⁷ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;        —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹) SO₂R⁶²; or        —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R²⁸ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)—OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R²⁹ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R³⁰ is H; alkyl; alkenyl; or aryl-lower alkyl;    -   R³¹ is H; alkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹, —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰ ₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R³² is H; lower alkyl; or aryl-lower alkyl;    -   R³³ is H; alkyl, alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COR⁶⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)—CONR⁵⁸R⁵⁹, —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R³⁴ is H; lower alkyl; aryl, or aryl-lower alkyl;    -   R³³ and R³⁴ taken together can form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;    -   R³⁵ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; (CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R³⁶ is H, alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴, —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷;        —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R³⁷ is H; F; Br; Cl; NO₂; CF₃; lower alkyl;        —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R³⁸ is H; F; Br, Cl; NO₂; CF₃; alkyl; alkenyl;        —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷;        —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R³⁹ is H; alkyl; alkenyl; or aryl-lower alkyl;    -   R⁴⁰ is H; alkyl; alkenyl; or aryl-lower alkyl;    -   R⁴¹ is H; F; Br; Cl; NO₂; CF₃; alkyl; alkenyl;        —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹) NR³³R³⁴;        —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁴² is H; F; Br; Cl; NO₂; CF₃; alkyl; alkenyl;        —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)NR²⁰CONR³³R⁸²;        —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;        —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or        —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁴³ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)₂SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁴⁴ is alkyl; alkenyl; —(CH₂)_(r)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(r)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(r)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(r)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(r)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR)₂;        —(CH₂)_(r)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁴⁵ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(s)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(s)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(s)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(s)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁴⁶ is H; alkyl; alkenyl; or —(CH₂)_(o)(CHR⁶¹)_(p)C₆H₄R⁸;    -   R⁴⁷ is H; alkyl; alkenyl; or —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    -   R⁴⁸ is H; lower alkyl; lower alkenyl; or aryl-lower alkyl;    -   R⁴⁹ is H; alkyl; alkenyl; —(CHR⁶¹)_(s)COOR⁵⁷;        (CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; (CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CHR⁶¹)_(s)SOR⁶²;        or —(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁵⁰ is H; lower alkyl; or aryl-lower alkyl;    -   R⁵¹ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;        —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂;        —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁵² is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶²)_(p)PO(OR⁶⁰)₂;        —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁵³ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂;        —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶¹; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁵⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; or —(CH₂)_(o)(CHRR⁶¹)_(s)C₆H₄R⁸;    -   R⁵⁵ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;        —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁷; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³;        —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)—COR⁶⁴;        —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷; or —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    -   R⁵⁶ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;        —(CH₂)_(m)(CHR⁶¹)OR⁵⁷; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³;        —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)—COR⁶⁴;        or —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹,    -   R⁵⁷ is H; lower alkyl; lower alkenyl; aryl lower alkyl; or        heteroaryl lower alkyl;    -   R⁵⁸ is H; lower alkyl; lower alkenyl; aryl; heteroaryl;        aryl-lower alkyl; or heteroaryl-lower alkyl;    -   R⁵⁹ is H; lower alkyl; lower alkenyl; aryl; heteroaryl;        aryl-lower alkyl; or heteroaryl-lower alkyl; or    -   R⁵⁸ and R⁵⁹ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;    -   R⁶⁰ is H; lower alkyl; lower alkenyl; aryl; or aryl-lower alkyl;    -   R⁶¹ is alkyl; alkenyl; aryl; heteroaryl; aryl-lower alkyl;        heteroaryl-lower alkyl; —(CH₂)_(m)OR⁵⁵; —(CH₂)_(m)NR³³R³⁴;        —(CH₂)_(m)OCONR⁷⁵R⁸²; —(CH₂)_(m)NR²⁰CONR⁷⁵R⁸²; —(CH₂)_(o)COOR³⁷;        —(CH₂)_(o)NR⁵⁸R⁵⁹; or —(CH₂)_(o)PO(COR⁶⁰)₂;    -   R⁶² is lower alkyl; lower alkenyl; aryl, heteroaryl; or        aryl-lower alkyl;    -   R⁶³ is H; lower alkyl; lower alkenyl; aryl, heteroaryl;        aryl-lower alkyl; heteroaryl-lower alkyl; —COR⁶⁴; —COOR⁵⁷;        —CONR⁵⁸R⁵⁹; —SO₂R⁶²; or —PO(OR⁶⁰)₂    -   R³⁴ and R⁶³ taken together can form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;    -   R⁶⁴ is H; lower alkyl; lower alkenyl; aryl; heteroaryl;        aryl-lower alkyl; heteroaryl-lower alkyl;        —(CH₂)_(p)(CHR⁶¹)_(s)OR⁶⁵; —(CH₂)_(p)(CHR⁶¹)_(s)SR⁶⁶; or        —(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;        —(CH₂)_(p)(CHR⁶¹)NR²CONR⁷⁸R⁸²;    -   R⁶⁵ is H; lower alkyl; lower alkenyl; aryl, aryl-lower alkyl;        heteroaryl-lower alkyl; —COR¹⁷; —COOR⁵⁷; or —CONR⁵⁸R⁵⁹;    -   R⁶⁶ is H; lower alkyl; lower alkenyl; aryl; aryl-lower alkyl;        heteroaryl-lower alkyl; or —CONR⁵⁸R⁵⁹;    -   m is 2-4; o is 0-4; p is 1-4; q is 0-2; r is 1 or 2; s is 0 or        1;    -   Z is a chain of n α-amino acid residues, n being the integer 12,        14 or 18 and the positions of said amino acid residues in said        chain being counted starting from the N-terminal amino acid,        whereby these amino acid residues are, depending on their        position in the chains, Gly, NMeGly, Pro or Pip, or of formula        -A-CO—, or of formula —B—CO—, or of one of the types    -   C: —NR²⁰CH(R⁷²)CO—;    -   D: —NR²⁰CH(R⁷³)CO—;    -   E: —NR²⁰CH(R⁷⁴)CO—;    -   F: —NR²⁰CH(R⁸⁴)CO—; and    -   H: —NR²⁰—CH(CO—)—(CH₂)₄₋₇—CH(CO—)—NR²⁰—;        —NR²⁰—CH(CO—)—(CH₂)_(p)SS(CH₂)_(p)—CH(CO—)—NR²⁰—;        —NR²⁰—CH(CO—)-(—(CH₂)_(p)NR²⁰CO(CH₂)_(p)—CH(CO—)—NR²⁰—; and        —NR²⁰—CH(CO—)-(—CH₂)_(p)NR²⁰CONR²⁰(CH₂)_(p)—CH(CO—)—NR²⁰—;    -   I: —NR⁸⁶CH₂CO—;    -   R⁷¹ is lower alkyl; lower alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁷⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)SR⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(p)(CHR⁶¹)₅OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)N²⁰CONR³³R⁸²;        —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁷⁵; —(CH₂)_(p)CONR⁵⁸R⁵⁹;        —(CH₂)_(p)PO(OR⁶²)₂; —(CH₂)_(p)SO₂R⁶²; or        —(CH₂)_(o)—C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶;    -   R⁷² is H, lower alkyl; lower alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁸⁵;        or —(CH₂)_(p)(CHR⁶¹)_(s)SR⁸⁵;    -   R⁷³ is —(CH₂)_(o)R⁷⁷; —(CH₂)_(r)O(CH₂)_(o)R⁷⁷;        —(CH₂)_(r)S(CH₂)_(o)R⁷⁷; or —(CH₂)_(r)NR²⁰(CH₂)_(o)R⁷⁷;    -   R⁷⁴ is —(CH₂)_(p)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁷⁷R⁸⁰;        —(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(p)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰; —(CH₂)_(p)C₆H₄NR⁷⁸R⁷⁹;        —(CH₂)_(p)C₆H₄NR⁷⁷R⁸⁰; —(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;        —(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(p)C₆H₄N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰; —(CH₂)_(r)O(CH₂)_(m)NR⁷⁸R⁷⁹;        —(CH₂)_(r)O(CH₂)_(m)NR⁷⁷R⁸⁰;        —(CH₂)_(r)O(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(r)O(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(r)O(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;        —(CH₂)_(r)O(CH₂)_(m)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(r)O(CH₂)_(m)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰;        —(CH₂)_(r)O(CH₂)_(p)C₆H₄CNR⁷⁸R⁷⁹;        —(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(r)O(CH₂)_(p)C₆H₄C(NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;        —(CH₂)_(r)O(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(r)S(CH₂)_(m)NR⁷⁸R⁷⁹; —(CH₂)_(r)S(CH₂)_(m)NR⁷⁷R⁸⁰;        —(CH₂)_(r)S(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(r)S(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(r)S(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;        —(CH₂)_(r)S(CH₂)_(m)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(r)S(CH₂)_(m)N═(NR⁷⁸R⁷⁹)NR⁷⁹R⁸⁰;        —(CH₂)_(r)S(CH₂)_(p)C₆H₄CNR⁷⁸R⁷⁹;        —(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;        —(CH₂)_(r)S(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(p)NR⁸⁰COR⁶⁴; —(CH₂)_(p)NR⁸⁰COR⁷⁷;        —(CH₂)_(p)NR⁸⁰CONR⁷⁸R⁷⁹; —(CH₂)_(p)C₆H₄NR⁸⁰CONR⁷⁸R⁷⁹; or        —(CH₂)_(p)NR²⁰CO—[(CH₂)_(u)—X]_(t)—CH₃ where X is —O—; —NR²⁰—,        or —S—; u is 1-3, and t is 1-6;    -   R⁷⁵ is lower alkyl; lower alkenyl; or aryl-lower alkyl;    -   R³³ and R⁷⁵ taken together can form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;    -   R⁷⁵ and R⁸² taken together can form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;    -   R⁷⁶ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;        —(CH₂)_(o)R⁷²; —(CH₂)_(o)SR⁷²; —(CH₂)_(o)NR³³R³⁴;        —(CH₂)_(o)OCONR³³R⁷⁵; —(CH₂)_(o)NR²⁰CONR³³R⁸²; —(CH₂)_(o)COOR⁷⁵,        —(CH₂)_(o)CONR⁵⁸R⁵⁹; —(CH₂)_(o)PO(OR⁶⁰)₂; —(CH₂)_(p)SO₂R⁶²; or        —(CH₂)_(o)COR⁶⁴;    -   R⁷⁷ is —C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶; or a heteroaryl group of one of the        formulae

-   -   R⁷⁸ is H; lower alkyl; aryl; or aryl-lower alkyl;    -   R⁷⁸ and R⁸² taken together can form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;    -   R⁷⁹ is H; lower alkyl; aryl; or aryl-lower alkyl; or    -   R⁷⁸ and R⁷⁹, taken together, can be —(CH₂)₂₋₇—; —(CH₂)₂O(CH₂)₂—;        or —(CH₂)₂NR⁵⁷(CH₂)₂—;    -   R⁸⁰ is H; or lower alkyl;    -   R⁸¹ is H; lower alkyl; or aryl-lower alkyl;    -   R⁸² is H; lower alkyl; aryl; heteroaryl; or aryl-lower alkyl;    -   R³³ and R⁸² taken together can form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;    -   R⁸³ is H; lower alkyl; aryl; or —NR⁷⁸R⁷⁹;    -   R⁸⁴ is —(CH₂)_(m)(CHR₆₁)_(s)OH; —(CH₂)pCOOR₈₀;        —(CH₂)_(m)(CHR₆₁)_(s)SH; —(CH₂)_(p)CONR⁷⁸R⁷⁹;        —(CH₂)_(p)NR⁸⁰CONR⁷⁸R⁷⁹; —(CH₂)_(p)C₆H₄CONR⁷⁸R⁷⁹; or        —(CH₂)_(p)C₆H₄NR⁸⁰CONR⁷⁸R⁷⁹;    -   R⁸⁵ is lower alkyl; or lower alkenyl;    -   R⁸⁶ is R⁷⁴; —(CH₂)_(o)R⁷⁷; —(CH₂)_(o)—CHR³³R⁷⁵; or        —[(CH₂)_(u)—X′]_(t)—(CH₂)_(v)NR⁷⁸R⁷⁹; or        —[(CH₂)_(u)—X′]_(t)—(CH₂)_(v)—(═NR⁸⁰)NR⁷⁸R⁷⁹ where X is —O—,        —NR²⁰—, —S—; or —OCOO—, u is 1-3, t is 1-6, and v is 1-3;    -   with the proviso that in said chain of n α-amino acid residues Z        -   if n is 12, the amino acid residues in positions 1 to 12            are:            -   P1: of type C or of type D or of type E or of type F, or                the residue is Pro or Pip;            -   P2: of type E, or of type F or the residue is Gly,                NMeGly, Pro or Pip;            -   P3; or of type E, of type F;            -   P4: of type C, or of type D, or of type F, or the                residue is Gly or NMeGly;            -   P5: of type E, or of type D, or of type C, or of type F,                or of formula -A-CO— or the residue is Gly. NMeGly, Pro                or Pip;            -   P6: of type E, or of type F, or of formula —B—CO—, or                the residue is Gly or NMeGly;            -   P7: of type C, or of type E or of type F;            -   P8: of type D, or of type C, or the residue is Pro or                Pip;            -   P9: of type C, or of type D or of type F, or the residue                is Gly or NMeGly;            -   P10: of type D, or of type C, or the residue is Pro or                Pip;            -   P11: of type E or of type F or the residue is Gly or                NMeGly; and            -   P12: of type C or of type D or of type E or of type F,                or the residue is Pro or Pip; or            -   P4 and P9 and/or P2 and P11, taken together, can form a                group of type H;        -   at P4, P6. P9 also D-isomers being possible; and        -   if n is 14, the amino acid residues in positions 1 to 14            are:            -   P1: of type C, or of type D, or of type E, or of type F,                or the residue is Gly or NMeGly or Pro or Pip;            -   P2: of type E, or of type F, or of type I, or of type D;            -   P3: of type E, or of type F; or of type D, or of type C,                or the residue is Gly, NMeGly, Pro Pip;            -   P4: of type D, or of type C or of type F, or of type E;            -   P5: of type E, or of type F, or of type C or of type I;            -   P6: of type C, or of type D, or of type F, or the                residue is Gly, NMeGly, Pro or Pip;            -   P7: of type C, or of type D, or of formula A-CO—, or the                residue is Gly, NMeGly. Pro Pip;            -   P8: of type E, or of Type F, or of formula B—CO— or of                type I, or of type D, or the residue is Pro Pip;            -   P9: of type F, or of type E, or of type I, or of type D,                or the residue is Pro or Pip;            -   P10: of type F, or of type D, or of type C;            -   P11: of type D, or of type C, or of type F, or of type                E, or the residue is Pro or Pip;            -   P12: of type C, or of type D, or of type E, or of type                F;            -   P13: of type F, or of type E, or the residue is Gly.                NMeGly, Pro or Pip; and            -   P14; or of type F or of type E or of type C; or            -   P2 and P13 and/or P4 and P11, take together, can form a                group of type H;        -   at P4, P7, P8 and P11 D-isomers being possible;        -   with the further proviso that            -   the amino acid residue in P1 is Gly or NMeGly or Pip;                and/or            -   the amino acid residue in P2 is of type F or of type I;                and/or            -   the amino acid residue in P3 is of type F, or it is Gly,                NMeGly. Pro or Pip;        -   and/or            -   the amino acid residue in P4 is of type F; and/or            -   the amino acid residue in P5 is of type C or of type F                or of type 1; and/or            -   the amino acid residue in P6 is of type C or of type D,                or it is Gly or NMeGly;        -   and/or            -   the amino acid residue in P7 is of type C or of type D,                or it is Pro. Pip or NMeGly; and/or            -   the amino acid residue in P8 is of type I or of type D,                or it is Pro or Pip; and/or            -   the amino acid residue in P9 is of type F or of type I,                or it is Pip; and/or            -   the amino acid residue in P10 is of type F; and/or            -   the amino acid residue in P11 is of type C, or it is                Pip; and/or            -   the amino acid residue in P12 is of type C or of type F;                and/or            -   the amino acid residue in P13 is of type F, or it is                Gly, NMeGly or Pip; and/or            -   P2 and P13, taken together, form a group of type H;                and/or            -   P4 and P11, taken together, form a group of type H;                and/or            -   the amino acid residue in P4 is a D-isomer, and/or            -   the amino acid residue in P11 is a D-isomer, and        -   if n is 18, the amino acid residues in positions 1 to 18            are:            -   P1: of type D, or of type E, or of type C, or of type F;            -   P2: of type E, or of type F, or of type D;            -   P3: of type C, or of type D;            -   P4: of type E, or of type D, or of type F;            -   P5: of type D, or of type C, or of type E;            -   P6: of type C, or of type E, or of type F;            -   P7: of type C, or of type D, or of type E or of type F;            -   P8: of type F, or of type E, or the residue is Gly or                NMeGly;            -   P9: of type C, or of type D, or of type F;            -   P10: of type C, or of type E, or of formula -A-CO—, or                the residue is Pro or Pip;            -   P11: of type C, or of type E, or of formula —B—CO—, or                the residue is Gly, NMeGly, Pro or Pip;            -   P12: of type D, or of type C, or type F;            -   P13: of type E, or of type F, or the residue is Gly or                NMeGly;            -   P14: of type C, or of type D, or of type F;            -   P15: of type E, or of type F;            -   P16: of type D, or of type E, or of type F;            -   P17: of type E, or of type F; and            -   P18: of type C, or of type D, or of type E, or of type                F; or            -   P4 and P17 and/or P6 and P15 and/or P8 and P13, taken                together, can form a group of type H;        -   at P10, P11 and P12 also D-isomers being possible;        -   and pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention these β-hairpin peptidomimeticscan be prepared by a process which comprises

-   -   (a) coupling an appropriately functionalized solid support with        an appropriately N-protected derivative of that amino acid which        in the desired end-product is in position 5, 6 or 7 if n is 12,        or which in the desired end-product is in position 6, 7 or 8 if        n is 14, or which in the desired end-product is in position 8, 9        or 10 if n is 18, any functional group which may be present in        said N-protected amino acid derivative being likewise        appropriately protected;    -   (b) removing the N-protecting group from the product thus        obtained;    -   (c) coupling the product thus obtained with an appropriately        N-protected derivative of that amino acid which in the desired        end-product is one position nearer the N-terminal amino acid        residue, any functional group which may be present in said        N-protected amino acid derivative being likewise appropriately        protected;    -   (d) removing the N-protecting group from the product thus        obtained;    -   (e) repeating steps (c) and (d) until the N-terminal amino acid        residue has been introduced;    -   (f) coupling the product thus obtained with a compound of the        general formula

is as defined above and X is an N-protecting group or, alternatively, if

-   -   is to be group (a1) or (a2), above,        -   (fa) coupling the product obtained in step (e) with an            appropriately N-protected derivative of an amino acid of the            general formula

HOOC—B—H  III

or

HOOC-A-H  IV

-   -   wherein B and A are as defined above, any functional group which        may be present in said N-protected amino acid derivative being        likewise appropriately protected;        -   (fb) removing the N-protecting group from the product thus            obtained; and        -   (fc) coupling the product thus obtained with an            appropriately N-protected derivative of an amino acid of the            above general formula IV and, respectively, III, any            functional group which may be present in said N-protected            amino acid derivative being likewise appropriately            protected; and, respectively, if

-   -   is to be group (a3), above,        -   (fa′) coupling the product obtained in step (e) with an            appropriately N-protected derivative of an amino acid of the            above general formula III, any functional group which may be            present in said N-protected amino acid derivative being            likewise appropriately protected;        -   (fb′) removing the N-protecting group from the product thus            obtained; and        -   (fc′) coupling the product thus obtained with an            appropriately N-protected derivative of an amino acid of the            above general formula III, any functional group which may be            present in said N-protected amino acid derivative being            likewise appropriately protected;    -   (g) removing the N-protecting group from the product obtained in        step (f) or (fc) or (fc′);    -   (h) coupling the product thus obtained with an appropriately        N-protected derivative of that amino acid which in the desired        end-product is in position 12 if n is 12, or in position 14 if n        is 14, or in position 18 if n is 18, any functional group which        may be present in said N-protected amino acid derivative being        likewise appropriately protected;    -   (i) removing the N-protecting group from the product thus        obtained;    -   (j) coupling the product thus obtained with an appropriately        N-protected derivative of that amino acid which in the desired        end-product is one position farther away from position 12 if n        is 12 or in position 14 if n is 14, or from position 18 if n is        18, any functional group which may be present in said        N-protected amino acid derivative being likewise appropriately        protected;    -   (k) removing the N-protecting group from the product thus        obtained;    -   (l) repeating steps (j) and (k) until all amino acid residues        have been introduced;    -   (m) if desired, selectively deprotecting one or several        protected functional group(s) present in the molecule and        appropriately substituting the reactive group(s) thus liberated;    -   (n) if desired, forming one, two or three interstrand linkage(s)        between side-chains of appropriate amino acid residues at        opposite positions of the β-strand region;    -   (o) detaching the product thus obtained from the solid support;    -   (p) cyclizing the product cleaved from the solid support;    -   (q) removing any protecting groups present on functional groups        of any members of the chain of amino acid residues and, if        desired, any protecting group(s) which may in addition be        present in the molecule; and    -   (r) if desired, converting the product thus obtained into a        pharmaceutically acceptable salt or converting a        pharmaceutically acceptable, or unacceptable, salt thus obtained        into the corresponding free compound of formula I or into a        different, pharmaceutically acceptable, salt.

Alternatively, the peptidomimetics of the present invention can beprepared by

-   -   (a′) coupling an appropriately functionalized solid support with        a compound of the general formula

is as defined above and X is an N-protecting group or, alternatively, if

-   -   is to be group (a1) or (a2), above.        -   (a′a) coupling said appropriately functionalized solid            support with an appropriately N-protected derivative of an            amino acid of the general formula

HOOC—B—H  III

or

HOOC-A-H  IV

-   -   wherein B and A are as defined above, any functional group which        may be present in said N-protected amino acid derivative being        likewise appropriately protected;        -   (a′b) removing the N-protecting group from the product thus            obtained; and        -   (a′c) coupling the product thus obtained with an            appropriately N-protected derivative of an amino acid of the            above general formula IV and, respectively, III, any            functional group which may be present in said N-protected            amino acid derivative being likewise appropriately            protected; and, respectively, if

-   -   is to be group (a3), above,        -   (a′a′) coupling the product obtained in step (e) with an            appropriately N-protected derivative of an amino acid of the            above general formula II, any functional group which may be            present in said N-protected amino acid derivative being            likewise appropriately protected;        -   (a′b′) removing the N-protecting group from the product thus            obtained; and        -   (a′c′) coupling the product thus obtained with an            appropriately N-protected derivative of an amino acid of the            above general formula III, any functional group which may be            present in said N-protected amino acid derivative being            likewise appropriately protected;    -   (b′) removing the N-protecting group from the product obtained        in step (a′), (a′c) or (a′c′);    -   (c′) coupling the product thus obtained with an appropriately        N-protected derivative of that amino acid which in the desired        end-product is in position 12 if n is 12, or in position 14 if n        is 14, or in position 18 if n is 18, any functional group which        may be present in said N-protected amino acid derivative being        likewise appropriately protected;    -   (d′) removing the N-protecting group from the product thus        obtained;    -   (e′) coupling the product thus obtained with an appropriately        N-protected derivative of that amino acid which in the desired        end-product is one position farther away from position 12 if n        is 12, or from position 14 if n is 14, or from position 18 if n        is 18, any functional group which may be present in said        N-protected amino acid derivative being likewise appropriately        protected;    -   (f′) removing the N-protecting group from the product thus        obtained;    -   (g′) repeating steps (e′) and (f′) until all amino acid residues        have been introduced;    -   (h′) if desired, selectively deprotecting one or several        protected functional group(s) present in the molecule and        appropriately substituting the reactive group(s) thus liberated;    -   (i′) if desired forming one, two or three interstrand linkage(s)        between side-chains of appropriate amino acid residues at        opposite positions of the β-strand region;    -   (j′) detaching the product thus obtained from the solid support;    -   (k′) cyclizing the product cleaved from the solid support;    -   (l′) removing any protecting groups present on functional groups        of any members of the chain of amino acid residues and, if        desired, any protecting group(s) which may in addition be        present in the molecule; and    -   (m′) if desired, converting the product thus obtained into a        pharmaceutically acceptable salt or converting a        pharmaceutically acceptable, or unacceptable, salt thus obtained        into the corresponding free compound of formula I or into a        different, pharmaceutically acceptable, salt.

Introducing an amino acid residue of type I can, alternatively, beeffected by coupling with a leaving group-containing acylating agent,such as bromo, chloro or iodo acetic acid, followed by nucleophilicdisplacement with an amine of the formula H₂N—R⁸⁶ which, if necessary,is appropriately protected.

The peptidomimetics of the present invention can also be enantiomers ofthe compounds of formula I. These enantiomers can be prepared by amodification of the above processes in which enantiomers of all chiralstarting materials are used.

As used in this description, the term “alkyl”, taken alone or incombinations, designates saturated, straight-chain or branchedhydrocarbon radicals having up to 24, preferably up to 12, carbon atoms.Similarly, the term “alkenyl” designates straight chain or branchedhydrocarbon radicals having up to 24, preferably up to 12, carbon atomsand containing at least one or, depending on the chain length, up tofour olefinic double bonds. The term “lower” designates radicals andcompounds having up to 6 carbon atoms. Thus, for example, the term“lower alkyl” designates saturated, straight-chain or branchedhydrocarbon radicals having up to 6 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, tert.-butyl and thelike. The term “aryl” designates aromatic carbocyclic hydrocarbonradicals containing one or two six-membered rings, such as phenyl ornaphthyl, which may be substituted by up to three substituents such asBr, Cl, F, CF₃, NO₂, lower alkyl or lower alkenyl. The term “heteroaryl”designates aromatic heterocyclic radicals containing one or two five-and/or six-membered rings, at least one of them containing up to threeheteroatoms selected from the group consisting of O, S and N and saidring(s) being optionally substituted; representative examples of suchoptionally substituted heteroaryl radicals are indicated hereinabove inconnection with the definition of R⁷.

The structural element -A-CO— designates amino acid building blockswhich in combination with the structural element —B—CO— form templates(a1) and (a2). The structural element —B—CO— forms in combination withanother structural element —B—CO— template (a3). Preferably template(a3) is present only in formula I wherein n is 18 in chain Z. Templates(a) through (p) constitute building blocks which have an N-terminus anda C-terminus oriented in space in such a way that the distance betweenthose two groups may lie between 4.0-5.5A. A peptide chain Z is linkedto the C-terminus and the N-terminus of the templates (a) through (p)via the corresponding N- and C-termini so that the template and thechain form a cyclic structure such as that depicted in formula I. In acase as here where the distance between the N- and C-termini of thetemplate lies between 4.0-5.5A the template will induce the H-bondnetwork necessary for the formation of a β-hairpin conformation in thepeptide chain Z. Thus template and peptide chain form a β-hairpinmimetic.

The β-hairpin conformation is highly relevant for the CXCR4 antagonizingactivity of the β-hairpin mimetics of the present invention. Theβ-hairpin stabilizing conformational properties of the templates (a)through (p) play a key role not only for the selective CXCR4antagonizing activity but also for the synthesis process definedhereinabove, as incorporation of the templates at the beginning or nearthe middle of the linear protected peptide precursors enhancescyclization yields significantly.

Building blocks A1-A69 belong to a class of amino acids wherein theN-terminus is a secondary amine forming part of a ring. Among thegenetically encoded amino acids only proline falls into this class. Theconfiguration of building block A1 through A69 is (D), and they arecombined with a building block —B—CO— of (L)-configuration. Preferredcombinations for templates (a1) are -^(D)A1-CO—^(L)B—CO— to^(D)A69-CO—^(L)B—CO—. Thus, for example, ^(D)Pro-^(L)Pro constitutes theprototype of templates (a1). Less preferred, but possible arecombinations -^(L)A1-CO—^(D)B—CO— to ^(L)A69-CO—^(D)B—CO— formingtemplates (a2). Thus, for example, ^(L)Pro-^(D)Pro constitutes theprototype of template (a2).

It will be appreciated that building blocks -A1-CO— to -A69-CO— in whichA has (D)-configuration, are carrying a group R¹ at the α-position tothe N-terminus. The preferred values for R¹ are H and lower alkyl withthe most preferred values for R¹ being H and methyl. It will berecognized by those skilled in the art, that A1-A69 are shown in(D)-configuration which, for R¹ being H and methyl, corresponds to the(R)-configuration. Depending on the priority of other values for R¹according to the Cahn, Ingold and Prelog-rules, this configuration mayalso have to be expressed as (S).

In addition to R¹ building blocks -A1-CO— to -A69-CO— can carry anadditional substituent designated as R² to R¹⁷. This additionalsubstituent can be H, and if it is other than H, it is preferably asmall to medium-sized aliphatic or aromatic group. Examples of preferredvalues for R² to R⁷ are:

-   -   R²: H; lower alkyl; lower alkenyl; (CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); (CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); (CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; R⁵⁷: H; or lower alkyl);        (CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together from: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl;        or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR⁸² (where R²⁰: H; or lower lower alkyl; R³³:        H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or        R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); (CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R⁴: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁵: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower        alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; R⁵⁷: where H; or lower alkyl);        (CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³:        H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or        R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); (CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: alkyl; alkenyl; aryl; and aryl-lower alkyl;        heteroaryl-lower alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower        alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower        alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and        R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkenyl; or lower alkoxy).    -   R⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² where R²⁰: H; or lower lower alkyl; R³³:        H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or        R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁹R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl;        or F⁵⁸ and R⁵⁹ taken together from: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R⁷: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵: lower        alkyl; or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        (CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³:        H; or lower alkyl; or lower alkyl; R⁸²: H; or lower alkyl; or        R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(r)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl;        or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); (CH₂)rSO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵        (where R⁵⁵: lower alkyl; or lower alkenyl); (CH₂)_(o)SR⁵⁶ (where        R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        from: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together from:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁹: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower        alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R¹⁰: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R¹¹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R¹²: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(r)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶ (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R¹³: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(r)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R¹⁴: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R⁶⁴        (where: R²⁰: H; lower alkyl; R⁶⁴: lower alkyl; or lower        alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower        alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower        alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken        together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R¹⁵: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³⁴: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl); or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl;        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); (CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or        lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); particularly        favoured are NR²⁰CO lower alkyl (R²⁰═H; or lower alkyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R¹⁶: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)₂OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸²) where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R¹⁷: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷; lower alkyl;        alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(r)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).

Among the building blocks A1 to A69 the following are preferred: A5 withR² being H, A8, A22, A25, A38 with R² being H, A42, A47, and A50. Mostpreferred are building blocks of type A8′:

wherein R²⁰ is H or lower alkyl; and R⁶⁴ is alkyl; alkenyl; aryl;aryl-lower alkyl; or heteroaryl-lower alkyl; especially those whereinR⁶⁴ is n-hexyl (A8′-1); n-heptyl (A8′-2); 4-(phenyl)benzyl (A8′-3);diphenylmethyl (A8′-4); 3-amino-propyl (A8′-5); 5-amino-pentyl (A8′-6);methyl (A8′-7); ethyl (A8′-8); isopropyl (A8′-9); isobutyl (A8′-10);n-propyl (A8′-11); cyclohexyl (A8′-12); cyclohexylmethyl (A8′-13);n-butyl (A8′-14); phenyl (A8′-15); benzyl (A8′-16); (3-indolyl)methyl(A8′-17); 2-(3-indolyl)ethyl (A8′-18); (4-phenyl)phenyl (A8′-19); andn-nonyl (A8′-20).

Building block A70 belongs to the class of open-chain α-substitutedα-amino acids, building blocks A71 and A72 to the corresponding 1-aminoacid analogues and building blocks A73-A104 to the cyclic analogues ofA70. Such amino acid derivatives have been shown to constrain smallpeptides in well defined reverse turn or U-shaped conformations (C. M.Venkatachalam, Biopolymers, 1968, 6, 1425-1434; W. Kabsch, C Sander,Biopolymers 1983, 22, 2577). Such building blocks or templates areideally suited for the stabilization of β-hairpin conformations inpeptide loops (D. Obrecht, M. Altorfer, J. A. Robinson, “Novel PeptideMimetic Building Blocks and Strategies for Efficient Lead Finding”, Adv.Med. Chem. 1999, Vol. 4, 1-68; P. Balaram, “Non-standard amino acids inpeptide design and protein engineering”, Curr. Opin. Struct. Biol. 1992,2, 845-851; M. Crisma, G. Valle, C. Toniolo, S. Prasad, R. B. Rao, P.Balaram, “β-turn conformations in crystal structures of model peptidescontaining α,α-disubstituted amino acids”. Biopolymers 1995, 35, 1-9; V.J. Hruby, F. Al-Obeidi, W. Kazmierski, Biochem. J. 1990, 268, 249-262).

It has been shown that both enantiomers of building blocks -A70-CO— toA104-CO— in combination with a building block —B—CO— of L-configurationcan efficiently stabilize and induce β-hairpin conformations (D.Obrecht, M. Altorfer, J. A. Robinson, “Novel Peptide Mimetic BuildingBlocks and Strategies for Efficient Lead Finding”, Adv. Med. Chem. 1999,Vol. 4, 1-68; D. Obrecht, C. Spiegler, P. Schönholzer, K. Miller, H.Heimgartner, F. Stierli, Helv. Chim. Acta 1992, 75, 1666-1696; D.Obrecht, U. Bohdal, J. Daly, C. Lehmann, P. Schönholzer, K. Müller,Tetrahedron 1995, 51, 10883-10900: D. Obrecht, C. Lehmann, C. Ruffieux,P. Schönholzer, K. Müller, Helv. Chim. Acta 1995, 78, 1567-1587; D.Obrecht, U. Bohdal, C. Broger, D. Bur, C. Lehmann, R. Ruffieux, P.Schinholzer, C. Spiegler, Helv. Chim. Acta 1995, 78, 563-580; D.Obrecht, H. Karajiannis, C. Lehmann, P. Schönholzer, C. Spiegler, Helv.Chim. Acta 1995, 78, 703-714).

Thus, for the purposes of the present invention templates (a1) can alsoconsist of -A70-CO— to A104-CO— where building block A70 to A104 is ofeither (D)- or (L)-configuration, in combination with a building block—B—CO— of (L)-configuration.

Preferred values for R²⁰ in A70 to A104 are H or lower alkyl with methylbeing most preferred. Preferred values for R¹⁸, R¹⁹ and R²¹-R²⁹ inbuilding blocks A70 to A104 are the following:

-   -   R¹⁸: lower alkyl.    -   R¹⁹: lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)—; —(CH₂)₂S(CH₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(p)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(o)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R²¹: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        (CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        (CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R²²: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸⁷ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R²³: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        particularly favoured are NR²⁰CO lower alkyl (R²⁰═H; or lower        alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower        alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower        alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy);    -   R²⁴: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        particularly favoured are NR²⁰CO lower alkyl (R²⁰ ═H; or lower        alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower        alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower        alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy);    -   R²⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)CONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R²⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   Alternatively, R²⁵ and R²⁶ taken together can be —(CH₂)₂₋₆—;        —(CH₂)₂O (CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl).    -   R²⁷: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂N⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂; —; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S((CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R²⁸: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R²⁹: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        particularly favored are NR²⁰CO lower-alkyl (R²⁰═H; or lower        alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower        alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower        alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).

For templates (b) to (p), such as (b1) and (c1), the preferred valuesfor the various symbols are the following:

-   -   R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵        (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶        (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴        (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower        alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or        lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower        alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or        lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R²⁰: H; or lower alkyl.    -   R³⁰: H, methyl.    -   R³¹: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        (—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy); most preferred is 13 CH₂CONR⁵⁸R⁵⁹        (R⁵⁸: H; or lower alkyl; R⁵⁹: lower alkyl; or lower alkenyl).    -   R³²: H, methyl.    -   R³³: lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³⁴R⁶³ (where R³⁴:        lower alkyl; or lower alkenyl; R⁶³: H; or lower alkyl; or R³⁴        and R⁶³ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); (CH₂)_(m)OCONR⁷⁵R⁸² (where R⁷⁵: lower alkyl; or lower        alkenyl; R⁸²: H; or lower alkyl; or R⁷⁵ and R⁸² taken together        form: —(CH₂)₂₋₆; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR⁷⁸R⁸² (where R²⁰: H; or lower lower alkyl;        R⁷⁸: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R⁷⁸ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl).    -   R³⁴: H; or lower alkyl.    -   R³⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R²⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl).    -   R³⁶: lower alkyl; lower alkenyl; or aryl-lower alkyl.    -   R³⁷: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆−; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R³⁸: H; lower alkyl; lower alkenyl; —(CH)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁸ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl;        —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R³⁹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where:        R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl).    -   R⁴⁰: lower alkyl; lower alkenyl; or aryl-lower alkyl.    -   R⁴¹: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁴²: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁴³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² where R²⁰: H; or lower lower alkyl; R³³:        H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or        R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R⁴⁴: lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁸ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or        —(CH₂)_(o)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁴⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(s)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or        —(CH₂)_(s)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁴⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(s)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(s)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(s)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(s)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(s)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(s)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or        —(CH₂)_(s)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁴⁷: H; or OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl).    -   R⁴⁸: H; or lower alkyl.    -   R⁴⁹: H; lower alkyl; —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl;        or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl;        or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken        together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or        (CH₂)_(s)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁵⁰: H; methyl.    -   R⁵¹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); (CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or        —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁵²: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; R⁵⁷: H;        or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower        alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(p)COOR⁵⁷        (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(p)CONR⁵⁸R⁵⁹        (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower        alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); or —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F;        Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).    -   R⁵³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(p)CONR⁵⁸R⁵⁸ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or        —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁵⁴: lower alkyl; lower alkenyl; or aryl-lower alkyl.

Among the building blocks A70 to A104 the following are preferred: A74with R²² being H, A75, A76, A77 with R²² being H, A78 and A79.

The building block —B—CO— within templates (a1), (a2) and (a3)designates an L-amino acid residue. Preferred values for B are:—NR²⁰CH(R⁷¹)— and enantiomers of groups A5 with R² being H, A8, A22,A25, A38 with R² being H, A42, A47, and A50. Most preferred are

-   Ala L-Alanine-   Arg L-Arginine-   Asn L-Asparagine-   Cys L-Cysteine-   Gln L-Glutamine-   Gly Glycine-   His L-Histidine-   Ile L-Isoleucine-   Leu L-Leucine-   Lys L-Lysine-   Met L-Methionine-   Phe L-Phenylalanine-   Pro L-Proline-   Ser L-Serine-   Thr L-Threonine-   Trp L-Tryptophan-   Tyr L-Tyrosine-   Val L-Valine-   Cit L-Citrulline-   Orn L-Ornithine-   tBuA L-t-Butylalanine-   Sar Sarcosine-   t-BuG L-tert-Butylglycine-   4AmPhe L-para-Aminophenylalanine-   3AnPhe L-meta-Aminophenylalanine-   2AmPhe L-ortho-Aminophenylalanine-   Phe(mC(NH₂)═NH) L-meta-Amidinophenylalanine-   Phe(pC(NH₂)═NH) L-para-Amidinophenylalanine-   Phe(mNHC(NH₂)═NH) L-meta-Guanidinophenylalanine-   Phe(pNHC(NH₂)═NH) L-para-Guanidinophenylalanine-   Phg L-Phenylglycine-   Cha L-Cyclohexylalanine-   C₄al L-3-Cyclobutylalanine-   C₅al L-3-Cyclopentylalanine-   Nle L-Norleucine-   2-Nal L-2-Naphthylalanine-   1-Nal L-1-Naphthylalanine-   4Cl-Phe L-4-Chlorophenylalanine-   3Cl-Phe L-3-Chlorophenylalanine-   2Cl-Phe L-2-Chlorophenylalanine-   3,4Cl₂-Phe L-3,4-Dichlorophenylalanine-   4F-Phe L-4-Fluorophenylalanine-   3F-Phe L-3-Fluorophenylalanine-   2F-Phe L-2-Fluorophenylalanine-   Tic L-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid-   Thi L-β-2-Thienylalanine-   Tza L-2-Thiazolylalanine-   Mso L-Methionine sulfoxide-   AcLys L-N-Acetyllysine-   Dpr L-2,3-Diaminopropionic acid-   A₂Bu L-2,4-Diaminobutyric acid-   Dbu (S)-2,3-Diaminobutyric acid-   Abu γ-Aminobutyric acid (GABA)-   Aba ε-Aminohexanoic acid-   Aib α-Aminoisobutyric acid-   Y(Bzl) L-O-Benzyltyrosine-   Bip L-Biphenylalanine-   S(Bzl) L-O-Benzylserine-   T(Bzl) L-O-Benzylthreonine-   hCha L-Homo-cyclohexylalamine-   hCys L-Homo-cysteine-   hSer L-Homo-serine-   hArg L-Homo-arginine-   hPhe L-Homo-phenylalanine-   Bpa L-4-Benzoylphenylalanine-   Pip L-Pipecolic acid-   OctG L-Octylglycine-   MePhe L-N-Methylphenylalanine-   MeNle L-N-Methylnorleucine-   MeAla L-N-Methylalanine-   MeIle L-N-Methylisoleucine-   MeVal L-N-Methyaline-   MeLeu L-N-Methylleucine

In addition, the most preferred values for B also include groups of typeA8″ of (L)-configuration:

-   -   wherein R²⁰ is H or lower alkyl and R⁶⁴ is alkyl; alkenyl;        —[(CH₂)₂u-X]_(t)—CH₃ (where X is —O—; —NR²⁰—, or —S—; u=1-3, and        t=1-6), aryl; aryl-lower alkyl; or heteroaryl-lower alkyl;        especially those wherein R⁶⁴ is n-hexyl (A8″-21); n-heptyl        (A8″-22); 4-(phenyl)benzyl (A8″-23); diphenylmethyl (A8″-24);        3-amino-propyl (A8″-25); 5-amino-pentyl (A8″-26); methyl        (A8″-27); ethyl (A8″¹-28); isopropyl (A8″-29); isobutyl        (A8″-30); n-propyl (A8″-31); cyclohexyl (A8″-32);        cyclohexylmethyl (A8″-33); n-butyl (A8″-34); phenyl (A8″-35);        benzyl (A8″-36); (3-indolyl)methyl (A8″-37); 2-(3-indolyl)ethyl        (A8″-38); (4-phenyl)phenyl (A8″-39); n-nonyl (A8″-40);        CH₃—OCH₂CH₂—OCH₂— (A8″-41) and CH₃—(OCH₂CH₂)₂—OCH₂— (A8″-42).

The peptidic chain Z of the β-hairpin mimetics described herein isgenerally defined in terms of amino acid residues belonging to one ofthe following groups:

-   Group C —NR²⁰CH(R⁷²)CO—; “hydrophobic: small to medium-sized”-   Group D —NR²⁰CH(R⁷³)CO—; “hydrophobic: large aromatic or    heteroaromatic”-   Group E —NR²⁰CH(R⁷⁴)CO—; “polar-cationic” and “urea-derived”-   Group F —NR²⁰CH(R⁸⁴)CO—; “polar-non-charged or anionic”-   Group H —NR²⁰—CH(CO—)—(CH₂)₄₋₇—CH(CO—)—NR²⁰—;    —NR²⁰—CH(CO—)—(CH₂)_(p)SS(CH₂)_(p)—CH(CO—)—NR²⁰;    —NR²⁰—CH(CO—)-(—(CH₂)_(p)NR²⁰CO(CH₂)_(p)—CH(CO—)—NR²⁰—; and    —NR²⁰—CH(CO—)-(—(CH₂)_(p)NR²⁰CONR²⁰(CH₂)_(p)—CH(CO—)—NR²⁰—;    “interstrand linkage”-   Group I —NR⁸⁶CH₂CO—; “polar-cationic or hydrophobic”

Furthermore, the amino acid residues in chain Z can also be of formula-A-CO— or of formula —B—CO— wherein A and B are as defined above.Finally, Gly can also be an amino acid residue in chain Z, and Pro canbe an amino acid residue in chain Z, too, with the exception ofpositions where interstrand linkages (H) are possible.

Group C comprises amino acid residues with small to medium-sizedhydrophobic side chain groups according to the general definition forsubstituent R⁷². A hydrophobic residue refers to an amino acid sidechain that is uncharged at physiological pH and that is repelled byaqueous solution. Furthermore these side chains generally do not containhydrogen bond donor groups, such as (but not limited to) primary andsecondary amides, primary and secondary amines and the correspondingprotonated salts thereof, thiols, alcohols, phosphonates, phosphates,ureas or thioureas. However, they may contain hydrogen bond acceptorgroups such as ethers, thioethers, esters, tertiary amides, alkyl- oraryl phosphonates and phosphates or tertiary amines. Genetically encodedsmall-to-medium-sized amino acids include alanine, isoleucine, leucine,methionine and valine.

Group D comprises amino acid residues with aromatic and heteroaromaticside chain groups according to the general definition for substituentR⁷³. An aromatic amino acid residue refers to a hydrophobic amino acidhaving a side chain containing at least one ring having a conjugatedπ-electron system (aromatic group). In addition they may containhydrogen bond donor groups such as (but not limited to) primary andsecondary amides, primary and secondary amines and the correspondingprotonated salts thereof, thiols, alcohols, phosphonates, phosphates,ureas or thioureas, and hydrogen bond acceptor groups such as (but notlimited to) ethers, thioethers, esters, tetriary amides, alkyl- or arylphosphonates- and phosphates or tertiary amines. Genetically encodedaromatic amino acids include phenylalanine and tyrosine.

A heteroaromatic amino acid residue refers to a hydrophobic amino acidhaving a side chain containing at least one ring having a conjugatedn-system incorporating at least one heteroatom such as (but not limitedto) O, S and N according to the general definition for substituent R⁷⁷.In addition such residues may contain hydrogen bond donor groups such as(but not limited to) primary and secondary amides, primary and secondaryamines and the corresponding protonated salts thereof, thiols, alcohols,phosphonates, phosphates, ureas or thioureas, and hydrogen bond acceptorgroups such as (but not limited to) ethers, thioethers, esters, tetriaryamides, alkyl- or aryl phosphonates- and phosphates or tertiary amines.Genetically encoded heteroaromatic amino acids include tryptophan andhistidine.

Group E comprises amino acids containing side chains withpolar-cationic, acylamino- and urea-derived residues according to thegeneral definition for substituent R⁷⁴. Polar-cationic refers to a basicside chain which is protonated at physiological pH. Genetically encodedpolar-cationic amino acids include arginine, lysine and histidine.Citrulline is an example for an urea derived amino acid residue.

Group F comprises amino acids containing side chains withpolar-non-charged or anionic residues according to the generaldefinition for substituent R⁸⁴. A polar-non-charged or anionic residuerefers to a hydrophilic side chain that is uncharged and, respectivelyanionic at physiological pH (carboxylic acids being included), but thatis not repelled by aqueous solutions. Such side chains typically containhydrogen bond donor groups such as (but not limited to) primary andsecondary amides, carboxyclic acids and esters, primary and secondaryamines, thiols, alcohols, phosphonates, phosphates, ureas or thioureas.These groups can form hydrogen bond networks with water molecules. Inaddition they may also contain hydrogen bond acceptor groups such as(but not limited to) ethers, thioethers, esters, tetriary amides,carboxylic acids and carboxylates, alkyl- or aryl phosphonates- andphosphates or tertiary amines. Genetically encoded polar-non-chargedamino acids include asparagine, cysteine, glutamine, serine andthreonine, but also aspartic acid and glutamic acid.

Group H comprises side chains of preferably (L)-amino acids at oppositepositions of the β-strand region that can form an interstrand linkage.The most widely known linkage is the disulfide bridge formed bycysteines and homo-cysteines positioned at opposite positions of theβ-strand. Various methods are known to form disulfide linkages includingthose described by: J. P. Tam et al. Synthesis 1979, 955-957; Stewart etal., Solid Phase Peptide Synthesis, 2d Ed., Pierce Chemical Company,Ill., 1984; Ahmed et al. J. Biol. Chem. 1975, 250, 8477-8482; andPennington et al., Peptides, pages 164-166, Giralt and Andreu, Eds.,ESCOM Leiden, The Netherlands, 1990. Most advantageously, for the scopeof the present invention, disulfide linkages can be prepared usingacetamidomethyl (Acm)-protective groups for cysteine. A well establishedinterstrand linkage consists in linking ornithines and lysines,respectively, with glutamic and aspartic acid residues located atopposite β-strand positions by means of an amide bond formation.Preferred protective groups for the side chain amino-groups of ornithineand lysine are allyloxycarbonyl (Alloc) and allylesters for aspartic andglutamic acid. Finally, interstrand linkages can also be established bylinking the amino groups of lysine and ornithine located at oppositeβ-strand positions with reagents such as N,N-carbonylimidazole to formcyclic ureas.

Group I comprises glycine having the amino group substituted by chainscontaining polar-cationic or hydrophobic residues according to thegeneral definition for substituent R⁸⁶. Polar-cationic refers to a basicside chain which is protonated at physiological pH. A hydrophobicresidue refers to an amino acid side chain that is uncharged atphysiological pH and that is repelled by aqueous solution.

As mentioned earlier, positions for interstrand linkages are, if n is12, positions P4 and P9; and/or P2 and P11 taken together; if n is 14,positions P2 and P13 and/or P4 and P11; and, if n is 18, positions P4and P17 and/or P6 and P15 and/or P8 and P13 taken together. Suchinterstrand linkages are known to stabilize the β-hairpin conformationsand thus constitute an important structural element for the design ofβ-hairpin mimetics.

Most preferred amino acid residues in chain Z are those derived fromnatural α-amino acids. Hereinafter follows a list of amino acids which,or the residues of which, are suitable for the purposes of the presentinvention, the abbreviations corresponding to generally adopted usualpractice:

three letter code one letter code Ala L-Alanine A Arg L-Arginine R AsnL-Asparagine N Asp L-Aspartic acid D Cys L-Cysteine C Glu L-Glutamicacid E Gln L-Glutamine Q Gly Glycine G His L-Histidine H IleL-Isoleucine I Leu L-Leucine L Lys L-Lysine K Met L-Methionine M PheL-Phenylalanine F Pro L-Proline P ^(D)Pro D-Proline ^(D)P Ser L-Serine SThr L-Threonine T Trp L-Tryptophan W Tyr L-Tyrosine Y Val L-Valine V

Other α-amino acids which, or the residues of which, are suitable forthe purposes of the present invention include:

-   Cit L-Citrulline-   Orn L-Ornithine-   tBuA L-t-Butylalanine-   Sar Sarcosine-   Pen L-Penicillamine-   t-BuG L-tert.-Butylglycine-   4AmPhe L-para-Aminophenylalanine-   3AmPhe L-meta-Aminophenylalanine-   2AmPhe L-ortho-Aminophenylalanine-   Phe(mC(NH₂)═NH) L-meta-Amidinophenylalanine-   Phe(pC(NH₂)═NH) L-para-Amidinophenylalanine-   Phe(mNHC(NH₂)═NH) L-meta-Guanidinophenylalanine-   Phe(pNHC(NH₂)═NH) L-para-Guanidinophenylalanine-   Phg L-Phenylglycine-   Cha L-Cyclohexylalanine-   C₄al L-3-Cyclobutylalanine-   C₅al L-3-Cyclopentylalanine-   Nle L-Norleucine-   2-Nal L-2-Naphthylalanine-   1-Nal L-1-Naphthylalanine-   4Cl-Phe L-4-Chlorophenylalanine-   3Cl-Phe L-3-Chlorophenylalanine-   2Cl-Phe L-2-Chlorophenylalanine-   3,4Cl₂-Phe L-3,4-Dichlorophenylalanine-   4F-Phe L-4-Fluorophenylalanine-   3F-Phe L-3-Fluorophenylalanine-   2F-Phe L-2-Fluorophenylalanine-   Tic 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid-   Thi L-β-2-Thienylalanine-   Tza L-2-Thiazolylalanine-   Mso L-Methionine sulfoxide-   AcLys N-Acetyllysine-   A₂Bu 2,4-Diaminobutyric acid-   Dbu (S)-2,3-Diaminobutyric acid-   Abu γ-Aminobutyric acid (GABA)-   Aha ε-Aminohexanoic acid-   Aib α-Aminoisobutyric acid-   Y(Bzl) L-O-Benzyltyrosine-   Bip L-(4-phenyl)phenylalanine-   S(Bzl) L-O-Benzylserine-   T(Bzl) L-O-Benzylthreonine-   hCha L-Homo-cyclohexylalanine-   hCys L-Homo-cysteine-   hSer L-Homo-serine-   hArg L-Homo-arginine-   hPhe L-Homo-phenylalanine-   Bpa L-4-Benzoylphenylalanine-   4-AmPyrr1 (2S,4S)-4-Amino-pyrrolidine-L-carboxylic acid-   4-AmPyrr2 (2S,4R)-4-Amino-pyrrolidine-L-carboxylic acid-   4-PhePyrr1 (2S,5R)-4-Phenyl-pyrrolidine-L-carboxylic acid-   4-PhePyrr2 (2S,5S)-4-Phenyl-pyrrolidine-L-carboxylic acid-   5-PhePyrr1 (2S,5R)-5-Phenyl-pyrrolidine-L-carboxylic acid-   5-PhePyrr2 (2S,5S)-5-Phenyl-pyrrolidine-L-carboxylic acid-   Pro(4-OH) 1 (4S)-L-Hydroxyproline-   Pro(4-OH)₂ (4R)-L-Hydroxyproline-   Pip L-Pipecolic acid-   ^(D)Pip D-Pipecolic acid-   OctG L-Octylglycine-   NGly N-Methylglycine-   MePhe L-N-Methylphenylalanine-   MeNle L-N-Methylnorleucine-   MeAla L-N-Methylalanine-   MeIle L-N-Methylisoleucine-   MeVal L-N-Methylvaline-   MeLeu L-N-Methylleucine-   DimK L-(N′,N′Dimethyl)-lysine-   Lpzp L-piperazinic acid-   Dpzp D-piperazinic acid-   Isom L-(N′,N′-diisobutyl)-ornithine-   PipAla L-2-(4′-piperidinyl)-alanine-   PirrAla L-2-(3′-pyrrolidinyl)-alanine-   Ampc 4-Amino-piperidine-4-carboxylic acid-   NMeR L-N-Methylarginine-   NMeK L-N-Methyllysine-   NMePhe L-N-Methylphenylalanine-   IPegK    L-2-Amino-6-{2-[2-(2-methoxy-ethoxy)ethoxy]acetylamino}-hexanoic    acid-   SPegK L-2-Amino-6-[2-(2methoxy-ethoxy)-acetylamino]-hexanoic acid-   Dab L-1,4-Diamino-butyric acid-   IPegDab    L-2-Amino-4{2-[2-(2-methoxy-ethoxy)-ethoxy]-acetylamino}-butyric    acid-   SPegDab L-2-Amino-4[2-(2-methoxy-ethoxy)-acetylamino]butyric acid-   4-PyrAla L-2-(4′Pyridyl)-alanine-   OmPyr L-2-Amino-5-[(2′carbonylpyrazine)]amino-pentanoic acid-   BnG N-Benzylglycine-   (4-OH)BnG N-4-Hydroxy-benzylglycine-   IaG N-Isoamylglycine-   IbG N-Isobutlyglycine-   (EA)G N-(2-Aminoethyl)glycine-   (PrA)G N-(3-Amino-n-propyl)glycine-   (BA)G N-(4-Amino-n-butyl)glycine-   (PeA)G N-(5-Amino-n-pentyl)glycine-   (PEG₃-NH₂)G N—[(CH₂)₃O—(CH₂—CH₂O)₂—(CH₂)₃—NH₂]glycine-   (Pyrr)G N-{2-[2′-(1′-methyl-pyrrolidinyl)]-ethyl}-glycine-   (Dimp)G N-[2-(N′,N′-Dimethylamino)-propyl]-glycine-   (Im)G N-[3-(1′-imidazolyl)-propyl]-glycine-   (Pip)G N-{3-[1′-(4′-methylpiperazinyl)]-propyl}-glycine-   (Dime)G N-[2-(N′,N′-Dimethylamino)-ethyl]-glycine

Particularly preferred residues for group C are:

-   Ala L-Alanine-   Ile L-Isoleucine-   Leu L-Leucine-   Met L-Methionine-   Val L-Valine-   tBuA L-t-Butylalanine-   t-BuG L-tert.-Butylglycine-   Cha L-Cyclohexylalanine-   C₄al L-3-Cyclobutylalanine-   Csal L-3-Cyclopentylalanine-   Nle L-Norleucine-   hCha L-Homo-cyclohexylalanine-   OctG L-Octylglycine-   MePhe L-N-Methylphenylalanine-   MeNle L-N-Methylnorleucine-   MeAla L-N-Methylalanine-   MeIle L-N-Methylisoleucine-   MeVal L-N-Methylvaline-   MeLeu L-N-Methylleucine

Particularly preferred residues for group D are:

-   His L-Histidine-   Phe L-Phenylalanine-   Trp L-Tryptophan-   Tyr L-Tyrosine-   Phg L-Phenylglycine

2-Nal L-2-Naphthylalanine

-   1-Nal L-1-Naphthylalanine-   4Cl-Phe L-4-Chlorophenylalanine-   3Cl-Phe L-3-Chlorophenylalanine-   2Cl-Phe L-2-Chlorophenylalanine-   3,4Cl₂-Phe L-3,4-Dichlorophenylalanine-   4F-Phe L-4-Fluorophenylalanine-   3F-Phe L-3-Fluorophenylalanine-   2F-Phe L-2-Fluorophenylalanine-   Thi L-2-Thienylalanine-   Tza L-2-Thiazolylalanine-   Y(Bzl) L-O-Benzyltyrosine-   Bip L-Biphenylalanine-   S(Bzl) L-O-Benzylserine-   T(Bzl) L-O-Benzylthreonine-   hPhe L-Homo-phenylalanine-   Bpa L-4-Benzoylphenylalanine-   PirrAla L-2-(3′-pyrrolidinyl)-alanine-   NMePhe L-N-Methylphenylalanine-   4-PyrAla L-2-(4′Pyridyl)-alanine

Particularly preferred residues for group E are

-   Arg L-Arginine-   Lys L-Lysine-   Orn L-Ornithine-   Dpr L-2,3-Diaminopropionic acid-   Dbu (S)-2,3-Diaminobutyric acid-   Phe(pNH₂) L-para-Aminophenylalanine-   Phe(mNH₂) L-meta-Aminophenylalanine-   Phe(oNH₂) L-ortho-Aminophenylalanine-   hArg L-Homo-arginine-   Phe(mC(NH₂)═NH) L-meta-Amidinophenylalanine-   Phe(pC(NH₂)═NH) L-para-Amidinophenylalanine-   Phe(mNHC(NH₂)═NH) L-meta-Guanidinophenylalanine-   Phe(pNHC(NH₂)═NH) L-para-Guanidinophenylalanine-   DimK L-(N′,N′Dimethyl)-lysine-   Isom L-(N′,N′-diisobutyl)-ornithine-   NMeR L-N-Methylarginine-   NMeK L-N-Methyllysine-   IPegK    L-2-Amino-6-{2-[2-(2-methoxy-ethoxy)ethoxy]acetylamino}-hexanoic    acid-   SPegK L-2-Amino-6-[2-(2methoxy-ethoxy)-acetylamino]-hexanoic acid-   Dab L-1,4-Diamino-butyric acid-   IPegDab    L-2-Amino-4{2-[2-(2-methoxy-ethoxy)-ethoxy]-acetylamino}-butyric    acid-   SPegDab L-2-Amino-4[2-(2-methoxy-ethoxy)-acetylamino]butyric acid-   OmPyr L-2-Amino-5-[(2′carbonylpyrazine)]amino-pentanoic-   PipAla L-2-(4′-piperidinyl)-alanine

Particularly preferred residues for group F are

-   Asn L-Asparagine-   Asp L-Aspartic acid-   Cys L-Cysteine-   Gln L-Glutamine-   Glu L-Glutamic acid-   Ser L-Serine-   Thr L-Threonine-   Cit L-Citrulline-   Pen L-Penicillamine-   AcLys L-N-Acetyllysine-   hCys L-Homo-cysteine-   hSer L-Homo-serine

Particularly preferred residues for group I are

-   (EA)G N-(2-Aminoethyl)glycine-   (PrA)G N-(3-Amino-n-propyl)glycine-   (BA)G N-(4-Amino-n-butyl)glycine-   (PeA)G N-(5-Amino-n-pentyl)glycine-   (EGU)G N-(2-Guanidinoethyl)glycine-   (PrGU)G N-(3-Guanidino-n-propyl)glycine-   (BGU)G N-(4-Guanidino-n-butyl)glycine-   (PeGU)G N-(5-Guanidino-n-pentyl)glycine-   (PEG₃-NH₂)G N—[(CH₂)₃O—(CH₂—CH₂O)₂—(CH₂)₃—NH₂]glycine-   (Pyrr)G N-{2-[2′-(1′-methyl-pyrrolidinyl)]-ethyl}-glycine-   (Dimp)G N-[2-(N′,N′-Dimethylamino)-propyl]-glycine-   (Im)G N-[3-(1′-imidazolyl)-propyl]-glycine-   (Pip)G N-{3-[1′-(4′-methylpiperazinyl)]-propyl}-glycine-   (Dime)G N-[2-(N′,N′-Dimethylamino)-ethyl]-glycine

Generally, the peptidic chain Z within the β-hairpin mimetics of theinvention comprises 12, 14 or 18 amino acid residues. The positions P1to P12 and, respectively, to P14, or P18 of each amino acid residue inthe chain Z are unequivocally defined as follows: P1 represents thefirst amino acid in the chain Z that is coupled with its N-terminus tothe C-terminus of the templates (b)-(p), or of group —B—CO— in template(a1), or of group -A-CO— in template (a2), or of the group —B—CO—forming the C-terminus of template (a3); and P12 and, respectively, P14or P18 represents the last amino acid in the chain Z that is coupledwith its C-terminus to the N-terminus of the templates (b)-(p), or ofgroup -A-CO— in template (a1), or of group —B—CO— in template (a2), orof the group —B—CO— forming the N-terminus of template (a3). Each of thepositions P1 to P12 and, respectively, to P14 or P18 will preferablycontain an amino acid residue belonging to one of the above types C D,E, F, I, H, or of formula -A-CO— or of formula —B—CO—, or being Gly,NMeGly, Pro or Pip as follows:

If n is 12 the α-amino acid residues in positions 1 to 12 of the chain Zare preferably:

P1: of type C, or of type D, or of type F, or the residue is Pro or Pip;P2: of type E, or of type F, or the residue is Gly, NMeGly, Pro or Pip;P3: or of type E, of type F;P4: of type C, or of type D, or of type F, or the residue is Gly orNMeGly;P5: of type E, or of type D, or of type F, or the residue is Gly,NMeGly, Pro or Pip;P6: of type E, or of type F, or of formula —B—CO—, or the residue is Glyor NMeGly;P7: of type E, or of type F;P8: of type D, or of type C, or the residue is Pro or Pip;P9: of type C, or of type D, or of type F, or the residue is Gly orNMeGly;P10: of type D, or of type C, or the residue is Pro or Pip;P11: of type E, or of type F, or the residue is Gly or NMeGly; andP12: of type E or of type F, or the residue is Pro or Pip; orP4 and P9, taken together, form a group of type H;at P4, P6, P9 also D-isomers being possible.

If n is 12, the α-amino acid residues in positions 1 to 12 are mostpreferably:

P1: Tyr; P2: Arg, Gly; P3: Cit; P4: Val, Phe, Gly, Ile, Thr, Gln, Cys;P5: Arg; P6: Arg, ^(D)Arg; P7: Arg; P8: Trp, 2-Nal; P9: Val, Phe, Gly,Ile, Thr, Gln, Cys; P10: Tyr; P11: Cit, Gly; and P12: Lys; or

Cys at P4 and P9 form a disulfide bridge.

If n is 14, the α-amino acid residues in positions 1 to 14 of the chainZ are preferably:

P1: of type C, or of type D, or of type E, or of type F, or the residueis Gly or NMeGly or Pro or Pip;P2: of type E, or of type D, or of type F;P3: of type E, or of type F, or of type D, or of type C, or the residueis Pro or Pip;P4: of type D, or of type C, or of type F;P5: of type E, or of type F, or of type I;P6: of type C, or of type D, or of type F, or the residue is Gly,NMeGly, Pro or Pip;P7: of type C, or of type D, or of formula -A-CO—, or the residue isGly, NMeGly, Pro or Pip;P8: of type E, or of Type F, or of type D, or of type I, or thr residueis Pro or Pip;P9: of type F, or of type E, or of type D, or of type I, or the residueis Pro or Pip;P10: of type F, or of type D, or of type C;P11: of type D, or of type C, or of type F, or of type E;P12: of type C, or of type D, or of type F;P13: of type F, or of type E, or of type D, or of type C, or of type I,or the residue is Gly or NMeGly; andP14; or of type F, or of type E, or of type C; orP2 and P13 and/or P4 and P11, taken together, form a group of type H;at P4, P7, P8 or P11 D-isomers being possible;with the proviso thatthe amino acid residue in P1 is Gly or NMeGly or Pip; and/orthe amino acid residue in P2 is of type F; and/orthe amino acid residue in P3 is of type F, or it is Pro or Pip; and/orthe amino acid residue in P4 is of type F; and/orthe amino acid residue in P5 is of type F, or of type I; and/orthe amino acid residue in P6 is of type C, or of type D, or it is NMeGlyor Pip; and/orthe amino acid residue in P7 is of type C, or of Type D, or it isNMeGly, Pro or Pip; and/orthe amino acid residue in P8 is of type D, or of type I, or it is Pro orPip and/orthe amino acid residue in P9 is of type F, or of type I, or it is Pip;and/orthe amino acid residue in P10 is of type F; and/orthe amino acid residue in P11 is of type C; and/orthe amino acid residue in P12 is of type C, or of type F; and/orthe amino acid residue in P13 is of type F, or it is Gly or NMeGly;and/or P4 and P11, taken together, form a group of type H; and/orthe amino acid residue in P4 is a D-isomer; and/orthe amino acid residue in P11 is a D-isomer.

If n is 14, the α-amino acid residues in positions 1 to 14 are mostpreferably:

P1: Tyr, Gln, Arg, His, Ile, Trp, Thr, Glu, Ser, Val, Met, Phe, Gly,Asp, Leu, Pip;

P2: Arg, His, Lys, 4-PyrAla; P3: Cit; Arg, His, Ile, Tyr, Trp, Pro, Glu,Asn, Asp, Lys, Ala, Leu, Val, 4F-Phe, Met, Ser, Thr, Gln, Tyr;

P4: Val, Phe, Tyr, t-BuG, Cys, Ser, Dab, Glu;

P5: Arg, Dab, Ser, (EA)G; P6: Pro, Gly, Phe, Val, Cit, Ala; P7: ^(D)Pro,Pro, Gly, Val; P8: Arg, Tyr, Trp, Thr, 4F-Phe, Dab, 4-PyrAla, Isorn,(Im)G, Cit, His, IpegDab, ^(D)Pro; P9: Arg, (Pip)G, (EA)G, Orn, Pro;P10: 2-Nal, Trp, Tyr;

P11: Phe, Tyr, Val, t-BuG, Cys, Asn, Glu, Dab, Arg;

P12: Tyr, Cit; P13: Cit, Gln, Arg, His, Tyr, Asn, Asp, Lys, Ala, Ser,Leu, Met, NMeGly, Thr, Cys; and P14: Lys, Glu, Gln, Asn, Asp, Ala, Ser,NMeK;

with the Proviso thatthe amino acid residue in P1 is Pip or Gly; and orthe amino acid residue in P3 is Glu, Asn, Asp, Thr, or Gln; and/orthe amino acid residue in P4 is Cys, Ser, or Glu; and/orthe amino acid residue in P5 is Ser or (EA)G; and/orthe amino acid residue in P6 is Phe, Val, or Ala; and/orthe amino acid residue in P7 is Val, Pro, or ^(D)Pro; and/orthe amino acid residue in P8 is Tyr, Trp, 4F-Phe, 4-PyrAla, (Im)G, Hisor ^(D)Pro; and/orthe amino acid residue in P9 is (EA)G; and/orthe amino acid in P10 is Val or t-BuG; and/orthe amino acid residue in P12 is Tyr or Cit; and/orthe amino acid residue in P13 is Glu, Gln, Asp, Asn, Ser, Thr, Cys, orNMeGly; and/orCys at P4 and P11 form a disulfide bridge; and/orGlu at P4 and Dab at P11 form a lactam bridge; and/orDab at P4 and Glu at P11 form a lactam bridge

If n is 18, the amino acid residues in position 1-18 are mostpreferably:

P1: of type D, or of type E;P2: of type E, or of type F;P3: of type C, or of type D;P4: of type E, or of type F;P5: of type D, or of type E;P6: of type E, or of type F;P7: of type E, or of type F;P8: of type E, or of type F, or the residue is Gly or NMeGly;P9: of type D;P10: of type E, or of formula -A1-A69-CO—, or the residue is Pro or Pip;P11: of type E, or of formula —B—CO—, or the residue is Gly, NMeGly, Proor Pip;P12: of type D;P13: of type F, or of type E, or the residue is Gly or NMeGly;P14: of type C, or of type D;P15: of type E, or of type F;P16: of type E or of type F;P17: of type E, or of type F; andP18: of Type C or of type D or of type E or of Type F; orP4 and P17 and/or P6 and P15 and/or P8 and P13, taken together, form agroup of type H;at P10, P11 and P12 also D-isomers being possible.

If n is 18, the α-amino acid residues in positions 1 to 18 are mostpreferably:

P1: Arg; P2: Arg; P3: 2-Nal, Trp, Tyr; P4: Cys; P5: Tyr;

P6: Cit, Gln. Arg;

P7: Lys; P8: Cys, Gly; P9: Tyr; P10: Lys, ^(D)Lys, ^(D)Pro; P11: Gly,Pro, ^(D)Pro; P12: Tyr; P13: Cys, Gly; P14: Tyr; P15: Arg; P16: Cit,Thr, Lys; P17: Cys; and P18: Arg; or

Cys at P4 and P17 and/or at P8 andP13 form a disulfide bridge.

Particularly preferred β-peptidomimetics of the invention include thosedescribed in Examples 21, 22, 38, 45, 51, 52 53, 55, 56, 60, 61, 68, 75,84, 85, 87, 101, 102, 105, 110, 120, 132, 147, 151, 152 and 160.

The processes of the invention can advantageously be carried out asparallel array syntheses to yield libraries of template-fixed β-hairpinpeptidomimetics of the above general formula I. Such parallel synthesesallow one to obtain arrays of numerous (normally 24 to 192, typically96) compounds of general formula I in high yields and defined purities,minimizing the formation of dimeric and polymeric by-products. Theproper choice of the functionalized solid-support (i.e. solid supportplus linker molecule), templates and site of cyclization play therebykey roles.

The functionalized solid support is conveniently derived frompolystyrene crosslinked with, preferably 1-5%, divinylbenzene;polystyrene coated with polyethyleneglycol spacers (Tentagel®); andpolyacrylamide resins (see also Obrecht, D.; Villalgordo, J.-M,“Solid-Supported Combinatorial and Parallel Synthesis ofSmall-Molecular-Weight Compound Libraries”, Tetrahedron OrganicChemistry Series, Vol. 17, Pergamon, Elsevier Science, 1998).

The solid support is functionalized by means of a linker, i.e. abifunctional spacer molecule which contains on one end an anchoringgroup for attachment to the solid support and on the other end aselectively cleavable functional group used for the subsequent chemicaltransformations and cleavage procedures. For the purposes of the presentinvention two types of linkers are used:

Type 1 linkers are designed to release the amide group under acidconditions (Rink H, Tetrahedron Lett. 1987, 28, 3783-3790). Linkers ofthis kind form amides of the carboxyl group of the amino acids; examplesof resins functionalized by such linker structures include4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido)aminomethyl]PS resin,4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido)aminomethyl]-4-methylbenzydrylaminePS resin (Rink amide MBHA PS Resin), and4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido)aminomethyl]benzhydrylaminePS-resin (Rink amide BHA PS resin). Preferably, the support is derivedfrom polystyrene crosslinked with, most preferably 1-5%, divinylbenzeneand functionalized by means of the4-(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido) linker.

Type 2 linkers are designed to eventually release the carboxyl groupunder acidic conditions. Linkers of this kind form acid-labile esterswith the carboxyl group of the amino acids, usually acid-labile benzyl,benzhydryl and trityl esters; examples of such linker structures include2-methoxy-4-hydroxymethylphenoxy (Sasrin® linker),4-(2,4-dimethoxyphenyl-hydroxymethyl)-phenoxy (Rink linker),4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid (HMPB linker), trityland 2-chlorotrityl. Preferably, the support is derived from polystyrenecrosslinked with, most preferably 1-5%, divinylbenzene andfunctionalized by means of the 2-chlorotrityl linker.

When carried out as a parallel array syntheses the processes of theinvention can be advantageously carried out as described herein belowbut it will be immediately apparent to those skilled in the art howthese procedures will have to be modified in case it is desired tosynthesize one single compound of the above formula I.

A number of reaction vessels (normally 24 to 192, typically 96) equal tothe total number of compounds to be synthesized by the parallel methodare loaded with 25 to 1000 mg, preferably 100 mg, of the appropriatefunctionalized solid support, preferably 1 to 3% cross-linkedpolystyrene or Tentagel resin.

The solvent to be used must be capable of swelling the resin andincludes, but is not limited to, dichloromethane (DCM),dimethylformamide (DMF), N-methylpyrrolidone (NMP), dioxane, toluene,tetrahydrofuran (THF), ethanol (EtOH), trifluoroethanol (TFE),isopropylalcohol and the like. Solvent mixtures containing as at leastone component a polar solvent (e.g. 20% TFE/DCM, 35% THF/NMP) arebeneficial for ensuring high reactivity and solvation of the resin-boundpeptide chains (Fields, G. B., Fields, C. G., J. Am. Chem. Soc. 1991,113, 4202-4207).

With the development of various linkers that release the C-terminalcarboxylic acid group under mild acidic conditions, not affectingacid-labile groups protecting functional groups in the side chain(s),considerable progresses have been made in the synthesis of protectedpeptide fragments. The 2-methoxy-4-hydroxybenzylalcohol-derived linker(Sasrin® linker, Mergler et al., Tetrahedron Lett. 1988, 29 4005-4008)is cleavable with diluted trifluoroacetic acid (0.5-1% TFA in DCM) andis stable to Fmoc deprotection conditions during the peptide synthesis,Boc/tBu-based additional protecting groups being compatible with thisprotection scheme. Other linkers which are suitable for the process ofthe invention include the super acid labile4-(2,4-dimethoxyphenyl-hydroxymethyl)-phenoxy linker (Rink linker, Rink,H. Tetrahedron Lett. 1987, 28, 3787-3790), where the removal of thepeptide requires 10% acetic acid in DCM or 0.2% trifluoroacetic acid inDCM; the 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid-derived linker(HMPB-linker, Flörsheimer & Riniker, Peptides 1991, 1990 131) which isalso cleaved with 1% TFA/DCM in order to yield a peptide fragmentcontaining all acid labile side-chain protective groups; and, inaddition, the 2-chlorotritylchloride linker (Barlos et al., TetrahedronLett. 1989, 30, 3943-3946), which allows the peptide detachment using amixture of glacial acetic acid/trifluoroethanol/DCM (1:2:7) for 30 min.

Suitable protecting groups for amino acids and, respectively, for theirresidues are, for example,

-   -   for the amino group (as is present e.g. also in the side-chain        of lysine)        Cbz benzyloxycarbonyl        Boc tert.-butyloxycarbonyl        Fmoc 9-fluorenylmethoxycarbonyl        Alloc allyloxycarbonyl        Teoc trimethylsilylethoxycarbonyl        Tcc trichloroethoxycarbonyl        Nps o-nitrophenylsulfonyl;        Trt triphenymethyl or trityl    -   for the carboxyl group (as is present e.g. also in the        side-chain of aspartic and glutamic acid) by conversion into        esters with the alcohol components        tBu tert.-butyl        Bn benzyl        Me methyl

Ph Phenyl Pac Phenacyl

-   -   Allyl        Tse trimethylsilylethyl        Tce trichloroethyl;    -   for the guanidino group (as is present e.g. in the side-chain of        arginine)        Pmc 2,2,5,7,8-pentamethylchroman-6-sulfonyl        Ts tosyl (i.e. p-toluenesulfonyl)        Cbz benzyloxycarbonyl        Pbf Pentamethyldihydrobenzofuran-5-sulfonyl    -   for the hydroxy group (as is present e.g. in the side-chain of        threonine and serine)        tBu tert.-butyl        Bn benzyl        Trt trityl    -   and for the mercapto group (as is present e.g. in the side-chain        of cysteine)        Acm acetamidomethyl        tBu tert.-butyl        Bn benzyl        Trt trityl        Mtr 4-methoxytrityl.

The 9-fluorenylmethoxycarbonyl-(Fmoc)-protected amino acid derivativesare preferably used as the building blocks for the construction of thetemplate-fixed β-hairpin loop mimetics of formula I. For thedeprotection, i.e. cleaving off of the Fmoc group, 20% piperidine in DMFor 2% DBU/2% piperidine in DMF can be used.

N-substituted glycine derivatives (type 1) used as building blocks forthe construction of certain compounds of formula I are derived from9-fluorenylmethoxycarbonyl-(Fmoc)-protected amino acid derivatives or,alternatively, built up in two steps from leaving group-containingglycine precursors, such as bromo, chloro or iodo acetic acid, andsuitable primary amine building blocks NH₂—R⁸⁶. The first synthesis stepconsists of the attachment of the leaving group-containing acetylatingagent, such as bromo acetic acid, to the resin bound intermediatethrough formation of the amide bond. The second reaction step—thenucleophilic displacement—is accomplished using the primary aminebuilding blocks, wherein the residues are, if necessary, suitablyprotected with groups as described above for side chains of amino acids.

For the incorporation of the N-substituted glycine derivatives asbuilding blocks into the template-fixed β-hairpin loop mimetics thegeneral synthesis procedure for assembling the hairpin mimetics is usedas described herein.

The quantity of the reactant, i.e. of the amino acid derivative, isusually 1 to 20 equivalents based on the milliequivalents per gram(meq/g) loading of the functionalized solid support (typically 0.1 to2.85 meq/g for polystyrene resins) originally weighed into the reactiontube. Additional equivalents of reactants can be used, if required, todrive the reaction to completion in a reasonable time. The reactiontubes, in combination with the holder block and the manifold, arereinserted into the reservoir block and the apparatus is fastenedtogether. Gas flow through the manifold is initiated to provide acontrolled environment, for example, nitrogen, argon, air and the like.The gas flow may also be heated or chilled prior to flow through themanifold. Heating or cooling of the reaction wells is achieved byheating the reaction block or cooling externally with isopropanol/dryice and the like to bring about the desired synthetic reactions.Agitation is achieved by shaking or magnetic stirring (within thereaction tube). The preferred workstations (without, however, beinglimited thereto) are Labsource's Combi-chem station and MultiSynTech's-Syro synthesizer.

Amide bond formation requires the activation of the α-carboxyl group forthe acylation step. When this activation is being carried out by meansof the commonly used carbodiimides such as dicyclohexylcarbodiimide(DCC, Sheehan & Hess, J. Am. Chem. Soc. 1955, 77, 1067-1068) ordiisopropylcarbodiimide (DIC, Sarantakis et al Biochem. Biophys. Res.Commun. 1976, 73, 336-342), the resulting dicyclohexylurea anddiisopropylurea is insoluble and, respectively, soluble in the solventsgenerally used. In a variation of the carbodiimide method1-hydroxybenzotriazole (HOBt, Kinig & Geiger, Chem. Ber 1970, 103,788-798) is included as an additive to the coupling mixture. HOBtprevents dehydration, suppresses racemization of the activated aminoacids and acts as a catalyst to improve the sluggish coupling reactions.Certain phosphonium reagents have been used as direct coupling reagents,such as benzotriazol-1-yl-oxy-tris-dimethylamino)-phosphoniumhexafluorophosphate (BOP, Castro et al., Tetrahedron Lett. 1975, 14,1219-1222; Synthesis, 1976, 751-752), orbenzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophoshate(Py-BOP, Coste et al., Tetrahedron Lett. 1990, 31, 205-208), or2-(1H-benzotriazol-1-yl-) 1,1,3,3-tetramethyluronium terafluoroborate(TBTU), or hexafluorophosphate (HBTU, Knorr et al., Tetrahedron Lett.1989, 30, 1927-1930); these phosphonium reagents are also suitable forin situ formation of HOBt esters with the protected amino acidderivatives. More recently diphenoxyphosphoryl azide (DPPA) orO-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TATU) orO-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU)/7-aza-1-hydroxy benzotriazole (HOAt, Carpinoet al., Tetrahedron Lett. 1994, 35, 2279-2281) have also been used ascoupling reagents.

Due to the fact that near-quantitative coupling reactions are essential,it is desirable to have experimental evidence for completion of thereactions. The ninhydrin test (Kaiser et al., Anal. Biochemistry 1970,34, 595), where a positive colorimetric response to an aliquot ofresin-bound peptide indicates qualitatively the presence of the primaryamine, can easily and quickly be performed after each coupling step.Fmoc chemistry allows the spectrophotometric detection of the Fmocchromophore when it is released with the base (Meienhofer et al., Int.J. Peptide Protein Res. 1979, 13, 35-42).

The resin-bound intermediate within each reaction tube is washed free ofexcess of retained reagents, of solvents, and of by-products byrepetitive exposure to pure solvent(s) by one of the two followingmethods:

-   -   1) The reaction wells are filled with solvent (preferably 5 ml),        the reaction tubes, in combination with the holder block and        manifold, are immersed and agitated for 5 to 300 minutes,        preferably 15 minutes, and drained by gravity followed by gas        pressure applied through the manifold inlet (while closing the        outlet) to expel the solvent;    -   2) The manifold is removed from the holder block, aliquots of        solvent (preferably 5 ml) are dispensed through the top of the        reaction tubes and drained by gravity through a filter into a        receiving vessel such as a test tube or vial.

Both of the above washing procedures are repeated up to about 50 times(preferably about 10 times), monitoring the efficiency of reagent,solvent, and by-product removal by methods such as TLC, GC, orinspection of the washings.

The above described procedure of reacting the resin-bound compound withreagents within the reaction wells followed by removal of excessreagents, by-products, and solvents is repeated with each successivetransformation until the final resin-bound fully protected linearpeptide has been obtained.

Before this fully protected linear peptide is detached from the solidsupport, it is possible, if desired, to selectively deprotect one orseveral protected functional group(s) present in the molecule and toappropriately substitute the reactive group(s) thus liberated. To thiseffect, the functional group(s) in question must initially be protectedby a protecting group which can be selectively removed without affectingthe remaining protecting groups present. Alloc (allyloxycarbonyl) is anexample for such an amino protecting group for which can be selectivelyremoved, e.g. by means of Pd° and phenylsilane in CH₂Cl₂, withoutaffecting the remaining protecting groups, such as Fmoc, present in themolecule. The reactive group thus liberated can then be treated with anagent suitable for introducing the desired substituent. Thus, forexample, an amino group can be acylated by means of an acylating agentcorresponding to the acyl substituent to be introduced. For theformation of the pegylated amino acids such as IPegK, or SPegK,preferably a solution of 5 equivalents of HATU(N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide) in dry DMF and a solution of 10 equivalentsof DIPEA (Diisopropyl ethaylamine) in dry DMF and 5 equivalents of2-[2-(2-methoxyethoxy)ethoxy]acetic acid (IPeg) and, respectively,2-(2-methoxyethoxy)acetic acid (sPeg), is applied to the liberated aminogroup of the appropriate amino acid side chain for 3 h. The procedure isthereafter repeated for another 3 h with a fresh solution of reagentsafter filtering and washing the resin.

Before this fully protected linear peptide is detached from the solidsupport, it is also possible, if desired, to form (an) interstrandlinkage(s) between side-chains of appropriate amino acid residues atopposite positions of the β-strand region.

Interstrand linkages and their formation have been discussed above, inconnection with the explanations made regarding groups of the type Hwhich can, for example, be disulfide bridges formed by cysteine andhomocysteine residues at opposite positions of the β-strand; or lactambridges formed by glutamic and aspartic acid residues linking ornithineand, respectively, lysine residues, or by glutamic acid residues linking2,4-diaminobutyric acid residues located at opposite β-strand positionsby amide bond formation. The formation of such interstrand linkages canbe effected by methods well known in the art.

For the formation of disulfide bridges preferably a solution of 10equivalents of iodine solution is applied in DMF or in a mixture ofCH₂Cl₂/MeOH for 1.5 h which is repeated is repeated for another 3 h witha fresh iodine solution after filtering of the iodine solution, or in amixture of DMSO and acetic acid solution, buffered with 5% with NaHCO₃to pH 5-6 for 4 h, or in water after adjusted to pH 8 with ammoniumhydroxide solution by stirring for 24 h, or in a solution of NMP andtri-n-butylphosphine (preferably 50 eq.).

For the formation of lactam bridges preferably a solution of 2equivalents of HATU(N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide) in dry DMF and a solution of 4 equivalentsof DIPEA (Diisopropyl ethaylamine) in dry DMF is applied for 16 h.

Detachment of the fully protected linear peptide from the solid supportis achieved by immersion of the reaction tubes, in combination with theholder block and manifold, in reaction wells containing a solution ofthe cleavage reagent (preferably 3 to 5 ml). Gas flow, temperaturecontrol, agitation, and reaction monitoring are implemented as describedabove and as desired to effect the detachment reaction. The reactiontubes, in combination with the holder block and manifold, aredisassembled from the reservoir block and raised above the solutionlevel but below the upper lip of the reaction wells, and gas pressure isapplied through the manifold inlet (while closing the outlet) toefficiently expel the final product solution into the reservoir wells.The resin remaining in the reaction tubes is then washed 2 to 5 times asabove with 3 to 5 ml of an appropriate solvent to extract (wash out) asmuch of the detached product as possible. The product solutions thusobtained are combined, taking care to avoid cross-mixing. The individualsolutions/extracts are then manipulated as needed to isolate the finalcompounds. Typical manipulations include, but are not limited to,evaporation, concentration, liquid/liquid extraction, acidification,basification, neutralization or additional reactions in solution.

The solutions containing fully protected linear peptide derivativeswhich have been cleaved off from the solid support and neutralized witha base, are evaporated. Cyclization is then effected in solution usingsolvents such as DCM, DMF, dioxane, THF and the like. Various couplingreagents which were mentioned earlier can be used for the cyclization.The duration of the cyclization is about 6-48 hours, preferably about 16hours. The progress of the reaction is followed, e.g. by RP-HPLC(Reverse Phase High Performance Liquid Chromatography). Then the solventis removed by evaporation, the fully protected cyclic peptide derivativeis dissolved in a solvent which is not miscible with water, such as DCM,and the solution is extracted with water or a mixture of water-misciblesolvents, in order to remove any excess of the coupling reagent.

Alternatively the detachment and complete deprotection of the fullyprotected peptide from the solid support can be achieved manually inglass vessels.

Finally, the fully protected peptide derivative is treated with 95% TFA,2.5% H₂O, 2.5% TIS or another combination of scavengers for effectingthe cleavage of protecting groups. The cleavage reaction time iscommonly 30 minutes to 12 hours, preferably about 2.5 hours. Thevolatiles are evaporated to dryness and the crude peptide is dissolvedin 20% AcOH in water and extracted with isopropyl ether or othersolvents which are suitable therefor. The aqueous layer is collected andevaporated to dryness, and the fully deprotected cyclic peptidederivative of formula I is obtained as end-product. Depending on itspurity, this peptide derivative can be used directly for biologicalassays, or it has to be further purified, for example by preparativeHPLC.

As mentioned earlier, it is thereafter possible, if desired, to converta fully deprotected product of formula I thus obtained into apharmaceutically acceptable salt or to convert a pharmaceuticallyacceptable, or unacceptable, salt thus obtained into the correspondingfree compound of formula I or into a different, pharmaceuticallyacceptable, salt. Any of these operations can be carried out by methodswell known in the art.

The template starting materials of formula II used in the processes ofthe invention, pre-starting materials therefor, and the preparation ofthese starting and pre-starting materials are described in InternationalApplication PCT/EP02/01711 of the same applicants, published as WO02/070547 A1.

The starting materials of formula H₂NR⁸⁶ are known or can be prepared bymethods which are well known in the art.

The β-hairpin peptidomimetics of the invention can be used in a widerange of applications in order to prevent HIV infections in healthyindividuals and slow or halt viral progression in infected patients, orwhere cancer is mediated or resulting from the CXCR4 receptor activity,or where immunological diseases are mediated or resulting from CXCR4receptor activity, or the β-hairpin peptidomimetics of the invention canbe used to treat immuno suppression, or they can be used duringapheresis collections of peripheral blood stem cells.

The β-hairpin peptidomimetics may be administered per se or may beapplied as an appropriate formulation together with carriers, diluentsor excipients well known in the art.

When used to treat or prevent HIV infections or cancer such as breastcancer, brain cancer, prostate cancer, lung cancer, kidney cancer,neuroblastoma, non-hodgkin's lymphoma, ovarian cancer, multiple myeloma,chronic lyphomphocytic leukemia, pancreatic cancer, melanoma,angiogenesis, and haematopoetic tissues; or inflammatory disorders suchas asthma, allergic rhinitis, hypersensitivity lung diseases,hypersensitivity pneumonitis, eosinophilic pneumonias, delayed-typehypersensitivity, interstitial lung disease (ILD), idiopathic pulmonaryfibrosis, ILD associated with rheumatoid arthritis, systemic lupuserythematosus, ankylosing sponylitis, systemic sclerosis, Sjogren'ssyndrome, systemic anaphylaxis or hypersensitivity responses, drugallergies, rheumatoid arthritis, psoriatic arthritis, systemic lupuserythematosus, myasthenia gravis, juvenile onset diabetes,glomerulonephritis, autoimmune throiditis, graft rejection, includingallograft rejection or graft-versus-host disease, inflammatory boweldiseases, inflammatory dernatoses; or to treat immunosuppression,including immunosuppression induced by chemotherapy, radiation therapyor graft/transplantation rejection, the β-hairpin peptidomimetics can beadministered singly, as mixtures of several, β-hairpin peptidomimetics,in combination with other anti-HIV agents, or antimicrobial agents oranti cancer agents or anti-inflammatory agents, or in combination withother pharmaceutically active agents. The β-hairpin peptidomimetics canbe administered per se or as pharmaceutical compositions.

Pharmaceutical compositions comprising β-hairpin peptidomimetics of theinvention may be manufactured by means of conventional mixing,dissolving, granulating, coated tablet-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes. Pharmaceuticalcompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients orauxilliaries which facilitate processing of the active β-hairpinpeptidomimetics into preparations which can be used pharmaceutically.Proper formulation depends upon the method of administration chosen.

For topical administration the β-hairpin peptidomimetics of theinvention may be formulated as solutions, gels, ointments, creams,suspensions, etc. as are well-known in the art.

Systemic formulations include those designed for administration byinjection, e.g. subcutaneous, intravenous, intramuscular, intrathecal orintraperitoneal injection, as well as those designed for transdermal,transmucosal, oral or pulmonary administration.

For injections, the β-hairpin peptidomimetics of the invention may beformulated in adequate solutions, preferably in physiologicallycompatible buffers such as Hink's solution, Ringer's solution, orphysiological saline buffer. The solutions may contain formulatoryagents such as suspending, stabilizing and/or dispersing agents.Alternatively, the β-hairpin peptidomimetics of the invention may be inpowder form for combination with a suitable vehicle, e.g., sterilepyrogen-free water, before use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation as known in the art.

For oral administration, the compounds can be readily formulated bycombining the active β-hairpin peptidomimetics of the invention withpharmaceutically acceptable carriers well known in the art. Suchcarriers enable the β-hairpin peptidomimetics of the invention to beformulated as tablets, pills, dragees, capsules, liquids, gels, syrups,slurries, suspensions etc., for oral ingestion by a patient to betreated. For oral formulations such as, for example, powders, capsulesand tablets, suitable excipients include fillers such as sugars, such aslactose, sucrose, mannitol and sorbitol; cellulose preparations such asmaize starch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulatingagents; and binding agents. If desired, desintegrating agents may beadded, such as cross-linked polyvinylpyrrolidones, agar, or alginic acidor a salt thereof, such as sodium alginate. If desired, solid dosageforms may be sugar-coated or enteric-coated using standard techniques.

For oral liquid preparations such as, for example, suspensions, elixirsand solutions, suitable carriers, excipients or diluents include water,glycols, oils, alcohols, etc. In addition, flavoring agents,preservatives, coloring agents and the like may be added.

For buccal administration, the composition may take the form of tablets,lozenges, etc. formulated as usual.

For administration by inhalation, the, β-hairpin peptidomimetics of theinvention are conveniently delivered in form of an aeorosol spray frompressurized packs or a nebulizer, with the use of a suitable propellant,e.g. dichlorodifluoromethane, trichlorofluoromethane, carbon dioxide oranother suitable gas. In the case of a pressurized aerosol the dose unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g. gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the β-hairpinpeptidomimetics of the invention and a suitable powder base such aslactose or starch.

The compounds may also be formulated in rectal or vaginal compositionssuch as suppositories together with appropriate suppository bases suchas cocoa butter or other glycerides.

In addition to the formulations described previously, the β-hairpinpeptidomimetics of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (e.g. subcutaneously or intramuscularly) or byintramuscular injection. For the manufacture of such depot preparationsthe β-hairpin peptidomimetics of the invention may be formulated withsuitable polymeric or hydrophobic materials (e.g. as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly soluble salts.

In addition, other pharmaceutical delivery systems may be employed suchas liposomes and emulsions well known in the art. Certain organicsolvents such as dimethylsulfoxide may also be employed. Additionally,the β-hairpin peptidomimetics of the invention may be delivered using asustained-release system, such as semipermeable matrices of solidpolymers containing the therapeutic agent. Various sustained-releasematerials have been established and are well known by those skilled inthe art. Sustained-release capsules may, depending on their chemicalnature, release the compounds for a few weeks up to over 100 days.Depending on the chemical nature and the biological stability of thetherapeutic agent, additional strategies for protein stabilization maybe employed.

As the β-hairpin pepdidomimetics of the invention may contain chargedresidues, they may be included in any of the above-describedformulations as such or as pharmaceutically acceptable salts.Pharmaceutically acceptable salts tend to be more soluble in aqueous andother protic solvents than are the corresponding free forms.

The β-hairpin peptidomimetics of the invention, or compositions thereof,will generally be used in an amount effective to achieve the intendedpurpose. It is to be understood that the amount used will depend on aparticular application.

For topical administration to treat or prevent HIV infections atherapeutically effective dose can be determined using, for example, thein vitro assays provided in the examples. The treatment may be appliedwhile the HIV infection is visible, or even when it is not visible. Anordinary skilled expert will be able to determine therapeuticallyeffective amounts to treat topical HIV infections without undueexperimentation.

For systemic administration, a therapeutically effective dose can beestimated initially from in vitro assays. For example, a dose can beformulated in animal models to achieve a circulating β-hairpinpeptidomimetic concentration range that includes the IC₅₀ as determinedin the cell culture (i.e. the concentration of a test compound that islethal to 50% of a cell culture). Such information can be used to moreaccurately determine useful doses in humans.

Initial dosages can also be determined from in vivo data, e.g. animalmodels, using techniques that are well known in the art. One havingordinary skill in the art could readily optimize administration tohumans based on animal data.

Dosage amounts for applications as anti-HIV agents may be adjustedindividually to provide plasma levels of the β-hairpin peptidomimeticsof the invention which are sufficient to maintain the therapeuticeffect. Therapeutically effective serum levels may be achieved byadministering multiple doses each day.

In cases of local administration or selective uptake, the effectivelocal concentration of the β-hairpin peptidomimetics of the inventionmay not be related to plasma concentration. One having the ordinaryskill in the art will be able to optimize therapeutically effectivelocal dosages without undue experimentation.

The amount of β-hairpin peptidomimetics administered will, of course, bedependent on the subject being treated, on the subject's weight, theseverity of the affliction, the manner of administration and thejudgement of the prescribing physician.

The anti-HIV therapy may be repeated intermittently while infections aredetectable or even when they are not detectable. The therapy may beprovided alone or in combination with other drugs, such as for exampleother anti-HIV agents or anti cancer agents, or other antimicrobialagents.

Normally, a therapeutically effective dose of the β-hairpinpeptidomimetics described herein will provide therapeutic benefitwithout causing substantial toxicity.

Toxicity of the β-hairpin peptidomimetics of the invention can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., by determining the LD₅₀ (the dose lethal to50% of the population) or the LD₁₀₀ (the dose lethal to 100% of thepopulation). The dose ratio between toxic and therapeutic effect is thetherapeutic index. Compounds which exhibit high therapeutic indices arepreferred. The data obtained from these cell culture assays and animalstudies can be used in formulating a dosage range that is not toxic foruse in humans. The dosage of the β-hairpin peptidomimetics of theinvention lies preferably within a range of circulating concentrationsthat include the effective dose with little or no toxicity. The dosagemay vary within the range depending upon the dosage form employed andthe route of administration utilized. The exact formulation, route ofadministration and dose can be chosen by the individual physician inview of the patient's condition (see, e.g. Fingl et al. 1975, In: ThePharmacological Basis of Therapeutics, Ch. 1, p. 1).

The following Examples illustrate the invention in more detail but arenot intended to limit its scope in any way. The following abbreviationsare used in these Examples:

-   -   HBTU: 1-benzotriazol-1-yl-tetramethylurounium        hexafluorophosphate (Knorr et al. Tetrahedron Lett. 1989, 30,        1927-1930);    -   HOBt: 1-hydroxybenzotriazole;    -   DIEA: diisopropylethylamine;    -   HOAT: 7-aza-1-hydroxybenzotriazole;    -   HATU: O-(7-aza-benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronoium        hexafluorophosphate (Carpino et al. Tetrahedron Lett. 1994, 35,        2279-2281).

EXAMPLES 1. Peptide Synthesis Coupling of the First Protected Amino AcidResidue to the Resin

0.5 g of 2-chlorotritylchloride resin (Barlos et al. Tetrahedron Lett.1989, 30, 3943-3946) (0.83 mMol/g, 0.415 mmol) was filled into a driedflask. The resin was suspended in CH₂Cl₂ (2.5 ml) and allowed to swellat room temperature under constant stirring for 30 min. The resin wastreated with 0.415 mMol (1 eq) of the first suitably protected aminoacid residue (see below) and 284 μl (4 eq) of diisopropylethylamine(DIEA) in CH₂Cl₂ (2.5 ml), the mixture was shaken at 25° C. for 4 hours.The resin colour changed to purple and the solution remained yellowish.The resin was shaken (CH₂Cl₂/MeOH/DIEA:17/2/1), 30 ml for 30 min; thenwashed in the following order with CH₂Cl₂ (1×), DMF (1×), CH₂Cl₂ (1×),MeOH (1×), CH₂Cl₂ (1×), MeOH (1×), CH₂Cl₂ (2×), Et₂O (2×) and driedunder vacuum for 6 hours. Loading was typically 0.6-0.7 mMol/g.

The following preloaded resins were prepared:Fmoc-ProO-chlorotritylresin, Fmoc-^(D)ProO-chlorotritylresin, andFmoc-S-(4-S-Alloc-amino)-ProO-chlorotritylresin.

Synthesis of the Fully Protected Peptide Fragment

The synthesis was carried out using a Syro-peptide synthesizer(Multisyntech) using 24 to 96 reaction vessels. In each vessel wereplaced 60 mg (weight of the resin before loading) of the above resin.The following reaction cycles were programmed and carried out:

Step Reagent Time 1 CH₂CL₂, wash and swell (manual) 3 × 1 min. 2 DMF,wash and swell 1 × 5 min. 3 40% piperidine/DMF 1 × 5 min. 4 DMF, wash 5× 2 min. 5 5 equiv. Fmoc amino acid/DMF + 1 × 120 min.  5 eq. HBTU + 5eq. HOBt + 5 eq. DIEA 6 DMF, wash 4 × 2 min. 7 CH₂Cl₂, wash (at the endof the synthesis) 3 × 2 min.

Steps 3 to 6 are repeated to add each amino-acid.

Pegylation of Side Chain Amino Functions with2-[2-(2-methoxyethoxy)ethox]acetic acid and 2-(2-methoxyethoxy)aceticacid

The resin (0.040 mmol) containing the peptide was swollen in 5 ml offreshly distilled CH₂Cl₂ for 30 min and then the palladium catalystPd(PPh₃)₄, 14 mg, 0.3 eq, was added followed by PhSiH₃, 0.8 mmol, 20 eq.The resin was shaken for 2 h and the reaction solution was filtered off.The reaction was repeated again by employing the same amount of reagentsand after 2 h the resin was washed with CH₂Cl₂ and DMF and finally withEt₂O. The resin was swollen again in freshly distilled CH₂Cl₂ (2 ml) for30 min, the solvent was filtered off and the resin swollen in DMF for 1h. A solution of DIPEA (10 eq) in 1 ml of DMF was added followed by theaddition of 2-[2-(2-methoxyethoxy)ethoxy]acetic acid or2-(2-methoxyethoxy)acetic acid (5 eq) and finally by a solution of HATU(5 eq) in 1 ml of DMF. The resin was shaken for 3 h and the reactionsolution was filtered off. The reaction was repeated again by employingthe same amount of reagents and after 3 h the resin was washed withCH₂Cl₂ and DMF and finally with Et₂O.

The pegylation procedure was performed optionally, after the synthesisof the fully protected peptide fragment had been terminated, and thensubsequently either Procedure A, Procedure B or Procedure C, asdescribed hereinbelow, was adopted, depending on whether no intertrandlinkages or disulfide, β-strand linkages or lactam β-strand linkageswere to be formed.

Procedure A: Cyclization and Work Up of Backbone Cyclized PeptidesCleavage of the Fully Protected Peptide Fragment

After completion of the synthesis, the resin was suspended in 1 ml (0.39mMol) of 1% TFA in CH₂Cl₂ (v/v) for 3 minutes, filtered and the filtratewas neutralized with 1 ml (1.17 mMol, 3 eq.) of 20% DIEA in CH₂Cl₂(v/v). This procedure was repeated twice to ensure completion of thecleavage. The filtrate was evaporated to dryness and the product wasfully deprotected [cleavage mixture containing 95% trifluoroacetic acid(TFA), 2.5% water and 2.5% triisopropylsilane (TIS)] to be analyzed byreverse phase-HPLC (column C₁₈) and ESI-MS to monitor the efficiency ofthe linear peptide synthesis.

Cyclization of the Linear Peptide

100 mg of the fully protected linear peptide were dissolved in DMF (9ml, conc. 10 mg/ml). Then 41.8 mg (0.110 mMol, 3 eq.) of HATU, 14.9 mg(0.110 mMol, 3 eq) of HOAt and 1 ml (0.584 mMol) of 10% DIEA in DMF(v/v) were added, and the mixture was vortexed at 20° C. for 16 hoursand subsequently concentrated under high vacuum. The residue waspartitioned between CH₂Cl₂ and H₂O/CH₃CN (90/10: v/v). The CH₂Cl₂ phasewas evaporated to yield the fully protected cyclic peptide.

Deprotection and Purification of the Cyclic Peptide

The cyclic peptide obtained was dissolved in 1 ml of the cleavagemixture containing 95% trifluoroacetic acid (TFA), 2.5% water and 2.5%triisopropylsilane (TIS). The mixture was left to stand at 20° C. for2.5 hours and then concentrated under vacuum. The residue was dissolvedin a solution of H₂O/acetic acid (75/25: v/v) and the mixture wasextracted with di-isopropylether.

The water phase was dried under vacuum and then the product was purifiedby preparative reverse phase HPLC.

After lyophilisation the products were obtained as white powders andanalysed by ESI-MS. The analytical data comprising purity afterpreparative HPLC and ESI-MS are shown in Tables 1, 2 and 3.

Analytical Method 1:

Analytical HPLC retention times (RT, in minutes) were determined using aVYDAC 218MS5215 column with the following solvents A (H₂O+0.02% TFA) andB (CH₃CN) and the gradient: 0 min: 92% A, 8% B; 8 min: 62% A 38% B; 9-12min: 0% A, 100% B.

Analytical Method 2:

Analytical HPLC retention times (RT, in minutes) were determined usingan EX (s.n. 217808-2 column with the following solvents A (H₂O+0.02%TFA) and B (CH₃CN) and the gradient: 0 min: 95% A, 5% B; 8 min: 30% A70% B; 9 min: 0% A, 100% B; 9-12 min: 95% A, 5% B.

Procedure B: Cyclization and Work Up of Backbone Cyclized PeptidesHaving Disulfide β-Strand Linkages Formation of Disulfide β-StrandLinkage

After completion of the synthesis, the resin was swelled in 3 ml of dryDMF for 1 h. Then 10 eq. of iodine solution in DMF (6 ml) were added tothe reactor, followed by stirring for 1.5 h. The resin was filtered anda fresh solution of iodine (10 eq.) in DMF (6 ml) was added, followed bystirring for another 3 h. The resin was filtered and washed with DMF(3×) and CH₂Cl₂ (3×).

Backbone Cyclization, Cleavage and Purification of the Peptide

After formation of the disulfide β-strand linkage, the resin wassuspended in 1 ml (0.39 mMol) of 1% TFA in CH₂Cl₂ (v/v) for 3 minutesand filtered, and the filtrate was neutralized with 1 (1.17 mMol, 3 eq.)of 20% DIEA in CH₂Cl₂ (v/v). This procedure was repeated twice to ensurecompletion of the cleavage.

The volatiles were removed and 6 ml dry DMF were added to the tube. Then2 eq. of HATU in dry DMF (1 ml) and 4 eq. of DIPEA in dry DMF (1 ml)were added to the peptide, followed by stirring for 16 h. The volatileswere evaporated to dryness. The crude cyclised peptide was dissolved in7 ml of CH₂Cl₂ and extracted with 10% acetonitrile in H₂O (4.5 ml) threetimes. The CH₂Cl₂ layer was evaporated to dryness. To deprotect thepeptide fully, 3 ml of cleavage cocktail TFA:TIS:H₂O (95:2.5:2.5) wereadded, and the mixture was kept for 2.5 h. The volatiles were evaporatedto dryness and the crude peptide was dissolved in 20% AcOH in water (7ml) and extracted with isopropyl ether (4 ml) for three times. Theaqueous layer was collected and evaporated to dryness, and the residuewas purified by preparative reverse phase HPLC.

After lyophilisation the products were obtained as white powders andanalysed by ESI-MS analytical method 1 or 2. The analytical datacomprising purity after preparative HPLC and ESI-MS are shown in Tablesand 1, 2 and 3.

Procedure C: Cyclization and Work Up of Backbone Cyclized PeptidesHaving Lactam β-Strand Linkages Formation of Lactam β-Strand Linkage

0.036 mmol of the resin was taken in a reactor and swelled in dry DMFfor 1 hr. To this 41.60 mg (1 eq.) of Pd(PPh₃)₄ and 0.133 ml (30 eq.) ofPhSiH₃ were added and stirred overnight. The resin was filtered andwashed thoroughly with DCM and DMF. The resin was swelled again in dryDMF for 1 hr. To this 1 ml DIPEA solution in DMF (24.64 μL of DIPEA in 1ml DMF, 4 eq.) was added followed by 1 ml HATU solution in DMF (27.37 mgof HATU, 2 eq.) and the final volume of the reaction mixture was 7 mland stirred overnight. The resin was washed thoroughly with DMF, CH₂Cl₂,DF, CH₂Cl₂.

Backbone Cyclization, Cleavage and Purification of the Peptide

The peptide was cleaved from the resin by 1% TFA in DCM and evaporatedto dryness and 8 ml of dry DMF added to the tube. 2 equivalents of HATUin dry DMF (1 ml) and 4 equivalents of DIPEA in dry DMF (1 ml) wereadded to the peptide and stirred for 16 h. The volatiles were evaporatedto dryness. The crude cyclised peptide was dissolved in 7 ml of DCM andextracted with 10% acetonitrile in H₂O (4.5 ml) three times. The DCMlayer was evaporated to dryness.

The crude cyclised peptide was dissolved in 7 ml of CH₂Cl₂ and extractedwith 10% acetonitrile in H₂O (4.5 ml) three times. The CH₂Cl₂ layer wasevaporated to dryness. To deprotect the peptide fully, 3 ml of cleavagecocktail TFA:TIS:H₂O (95:2.5:2.5) were added, and the mixture was keptfor 2.5 h. The volatiles were evaporated to dryness and the crudepeptide was dissolved in 20% AcOH in water (7 ml) and extracted withisopropyl ether (4 ml) for three times. The aqueous layer was collectedand evaporated to dryness, and the residue was purified by preparativereverse phase HPLC.

After lyophilisation the products were obtained as white powders andanalysed by ESI-MS analytical method 1 or 2. The analytical datacomprising purity after preparative HPLC and ESI-MS are shown in Tables1, 2 and 3.

Examples 1-6 and 8-11 (n=12) are shown in Table 1. The peptides weresynthesized starting with the amino acid Pro which was grafted to theresin. Starting resin was Fmoc-ProO-chlorotrityl resin, which wasprepared as described above. The linear peptides were synthesized onsolid support according to the procedure described above in thefollowing sequence:Resin-Pro-^(D)Pro-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafterthey were cleaved from the resin, cyclized, deprotected and purified asindicated in procedure A.

HPLC-retention times (minutes) were determined using the gradient method1 as described above:

-   -   Ex. 1 (4.98); Ex. 2 (4.62); Ex. 3 (5.63); Ex. 4 (5.33); Ex. 5        (5.12), Ex. 6 (4.75); Ex. 8 (5.08); Ex. 9 (6.17); Ex. 10 (6.28);        Ex. 11 (6.57).

Examples 7 and 12-14 (n=12) are shown in Table 1, The peptides weresynthesized starting with the amino acid Pro which was grafted to theresin. Starting resin was Fmoc-ProO-chlorotrityl resin, which wasprepared as described above. The linear peptides were synthesized onsolid support according to procedure described above in the followingsequence: Resin-Pro-^(D)Pro-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P3-P2-P.Thereafter the disulfide bridges were formed and the peptides werecleaved from the resin, cyclized, deprotected and purified as indicatedin procedure B.

HPLC-retention times (minutes) were determined using the gradient method1 described above:

-   -   Ex. 7 (4.48); Ex. 12 (4.83); Ex. 13 (5.30); Ex. 14 (4.08).

Examples 15-50 (n=14) are shown in Table 2. The peptides weresynthesized starting with the amino acid Pro which was grafted to theresin. Starting resin was Fmoc-ProO-chlorotrityl resin, which wasprepared as described above. The linear peptides were synthesized onsolid support according to procedure described above in the followingsequence:Resin-Pro-^(D)Pro-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Thereafter they were cleaved from the resin, cyclized, deprotected andpurified as indicated in procedure A.

HPLC-retention times (minutes) were determined using the gradient method1 described above:

-   -   Ex. 15 (5.35); Ex. 16 (5.48); Ex. 17 (5.85); Ex. 18 (5.78); Ex.        19 (4.82); Ex. 20 (5.33); Ex. 21 (5.77), Ex. 22 (5.85); Ex. 23        (6.22); Ex. 24 (6.22); Ex. 25 (4.48); Ex. 26 (5.08); Ex. 27        (6.17); Ex. 28 (6.28); Ex. 29 (6.57); Ex. 30 (6.73); Ex. 31        (5.60); Ex. 32 (5.58); Ex. 33 (5.85); Ex. 34 (6.20); Ex. 35        (6.33); Ex. 36 (5.43); Ex. 37 (5.85); Ex. 38 (5.92); Ex. 39        (5.47); Ex. 40 (6.0, 6.37)*; Ex. 41 (5.13); Ex. 42 (5.00); Ex.        43 (5.00); Ex. 44 (5.33, 5.67)*, Ex. 45 (5.03); Ex. 46 (4.75);        Ex. 47 (5.27); Ex. 48 (5.65, 6.08)*; Ex. 49 (5.03); Ex. 50        (5.75). * double peaks which show correct MS.

Examples 51-115, 117-141, 143-148 (n=14) are shown in Table 2. Thepeptides were synthesized starting with the amino acid Pro which wasgrafted to the resin. Starting resin was Fmoc-ProO-chlorotrityl resin,which was prepared as described above. The linear peptides weresynthesized on solid support according to procedure described above inthe following sequence:Resin-Pro-^(D)Pro-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Thereafter the disulfide bridges were formed, and the peptides werecleaved from the resin, cyclized, deprotected and purified as indicatedin procedure B.

HPLC-retention times (minutes) were determined using the gradient method1 for examples Ex 51-53, 138-139, for examples 54-115, 117-137, 140-141,143-148 gradient method 2, as described above:

-   -   Ex. 51 (4.68); Ex. 52 (4.67); Ex. 53 (5.05), Ex. 54 (3.16), Ex.        55 (3.41), Ex. 56 (3.07), Ex. 57 (2.95), Ex. 58 (2.99), Ex. 59        (3.18), Ex. 60 (3.16), Ex. 61 (3.27), Ex. 62 (2.91), Ex. 63        (2.88), Ex. 64 (2.88), Ex. 65 (2.98), Ex. 66 (3.17), Ex. 67        (2.93), Ex. 68 (2.91), Ex. 69 (2.90), Ex. 70 (2.88), Ex. 71        (3.08), Ex. 72 (3.00), Ex. 73 (3.14), Ex. 74 (3.02), Ex. 75        (2.99), Ex. 76 (3.56), Ex. 77 (3.14), Ex. 78 (3.18), Ex. 79        (3.02), Ex. 80 (3.18), Ex. 81 (3.13), Ex. 82 (3.38), Ex. 83        (3.27), Ex. 84 (3.32), Ex. 85 (3.37), Ex. 86 (3.57), Ex. 87        (3.35), Ex. 88 (3.08), Ex. 89 (3.10), Ex. 90 (3.14), Ex. 91        (3.18), Ex. 92 (3.17), Ex. 93 (3.25), Ex. 94 (3.10), Ex. 95        (3.18), Ex. 96 (3.15), Ex. 97 (3.31), Ex. 98 (3.26), Ex. 99        (3.32), Ex. 100 (3.28), Ex. 101 (3.83), Ex. 102 (3.00), Ex. 103        (3.29), Ex. 104 (2.98), Ex. 105 (2.77), Ex. 106 (2.74), Ex. 107        (3.000, Ex. 108 (2.81), Ex. 109 (2.69, 2.75), Ex. 110 (2.76,        2.82*), Ex. 111 (2.73, 2.78), Ex. 112 (2.71), Ex. 113 (2.51),        Ex. 114 (2.97), Ex. 115 (2.95), Ex. 117 (2.70), Ex. 118 (2.78),        Ex. 119 (2.83), Ex. 120 (2.80), Ex. 121 (3.09), Ex. 122 (3.45),        Ex. 123 (2.82), Ex. 124 (3.29), Ex. 125 (3.27), Ex. 126 (3.19),        Ex. 127 (3.05), Ex. 128 (3.86), Ex. 129 (4.76), Ex. 130 (4.43),        Ex. 131 (4.57), Ex. 132 (4.45), Ex. 133 (4.39), Ex. 134 (4.27),        Ex. 135 (4.33), Ex. 136 (2.75), Ex. 137 (2.72), Ex. 138 (4.75),        Ex. 139 (4.25), Ex. 140 (4.77), Ex. 141 (3.27), Ex. 143 (3.01),        Ex. 144 (3.24), Ex. 145 (2.84), Ex. 146 (2.80), Ex. 147 (2.91),        Ex. 148 (2.76). *double peaks which show correct MS.

Example 116 (n=14) is shown in Table 2. The peptide was synthesizedstarting with the amino acid Pro which was grafted to the resin.Starting resin was Fmoc-S-(4S-Alloc-amino)-ProO-chlorotrityl resin,which was prepared as described above. The linear peptide wassynthesized on solid support according to procedure described above inthe following sequence:Resin-S-(4-S-Alloc-amino)Pro-^(D)Pro-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Then the pegylation procedure was applied using2-[2-(2-methoxyethoxy)ethoxy]acetic acid resulting in ^(D)ProA8″-42 asthe template. Thereafter the disulfide bridge was formed, and thepeptide was cleaved from the resin, cyclized, deprotected and purifiedas indicated in procedure B.

HPLC-retention time (minutes) was determined using the gradient method 2as described above: Ex. 116 (3.00).

Example 142 (n=14) is shown in Table 2. The peptide was synthesizedstarting with the amino acid Pro which was grafted to the resin.Starting resin was Fmoc-ProO-chlorotrityl resin, which was prepared asdescribed above. The linear peptide was synthesized on solid supportaccording to procedure described above in the following sequence:Resin-Pro-^(D)Pro-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P3-P2-P1.Then the pegylation procedure was applied using2-[2-(2-methoxyethoxy)ethoxy]acetic acid. Thereafter the disulfidebridge was formed, and the peptide was cleaved from the resin, cyclized,deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the gradient method 2as described above: Ex. 142 (3.18).

Example 149 (n=14) is shown in Table 2. The peptide was synthesizedstarting with the amino acid Pro which was grafted to the resin.Starting resin was Fmoc-ProO-chlorotrityl resin, which was prepared asdescribed above. The linear peptide was synthesized on solid supportaccording to procedure described above in the following sequence:Resin-Pro-^(D)Gln-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P3-P2-P1.Thereafter the disulfide bridge was formed, and the peptide was cleavedfrom the resin, cyclized, deprotected and purified as indicated inprocedure B.

HPLC-retention time (minutes) was determined using the gradient method 2as described above: Ex. 149 (2.76).

Example 150 (n=14) is shown in table 2. The peptide was synthesizedstarting with the amino acid ^(D)Pro which was grafted to the resin.Starting resin was Fmoc-^(D)ProO-chlorotrityl resin, which was preparedas described above. The linear peptide was synthesized on solid supportaccording to procedure described above in the following sequence:Resin-^(D)Pro-Gly-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Thereafter the disulfide bridge was formed, and the peptide was cleavedfrom the resin, cyclized, deprotected and purified as indicated inprocedure B.

HPLC-retention time (minutes) was determined using the gradient method 2as described above: Ex. 150 (2.61).

Example 151 (n=14) is shown in Table 2. The peptide was synthesizedstarting with the amino acid Pro which was grafted to the resin.Starting resin was Fmoc-ProO-chlorotrityl resin, which was prepared asdescribed above. The linear peptide was synthesized on solid supportaccording to procedure described above in the following sequence:Resin-Pro-^(D)Pro-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P3-P2-P1.Thereafter the peptide was cleaved from the resin, cyclized, deprotectedand purified as indicated in procedure A.

HPLC-retention time (minutes) was determined using the gradient method 2as described above: Ex. 151 (2.86).

Examples 152-153 (n=14) are shown in Table 2. The peptides weresynthesized starting with the amino acid Pro which was grafted to theresin. Starting resin was Fmoc-ProO-chlorotrityl resin, which wasprepared as described above. The linear peptides were synthesized onsolid support according to procedure described above in the followingsequence:Resin-Pro-^(D)-Pro-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Thereafter the lactam bridges were formed, and the peptides were cleavedfrom the resin, cyclized, deprotected and purified as indicated inprocedure C.

HPLC-retention times (minutes) were determined using the gradient method2 as described above:

-   -   Ex. 152 (2.87), Ex. 153 (2.87, 2.88*). *double peaks which show        correct MS.

Examples 154-155 (n=18) are shown in Table 3. The peptides weresynthesized starting with the amino acid ^(D)Pro which was grafted tothe resin. Starting resin was Fmoc-^(D)ProO-chlorotrityl resin, whichwas prepared as described above. The linear peptides were synthesized onsolid support according to procedure described above in the followingsequence:Resin-^(D)Pro-Gly-P18-P17-P16-P15-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Thereafter the disulfide bridges were formed using the followingprocedure:

For the formation of the disulfide bridge at position P4 and P17 theprotected cyclic peptide (36 μmol) was swelled in dry DMF for 1 h. TheDMF was drained off and was replaced by 2 ml NMP and 444 μltri-n-butylphosphine (50 eq.) under argon. The resin was shaken for 2 h.

The solvents were removed and the resin was washed once with 5 ml NMP.Thereafter the resin was shaken again with 2 ml NMP and 444 μltri-n-butylphosphine (50 eq.) under argon for 2 h. The resin was washedwith DMF and transferred with 90 ml DMF into a 250 ml flask. 1 mmol (330mg) [K₃Fe(CN)₆] in 10 ml water was added and the suspension was agitatedgently overnight at 25° C. in the dark. The resin was transferred into areactor and was washed with once with 7 ml water and twice with 5 mlDMF.

For the formation of the second disulfide bridge at position P8 and P13the peptide was treated with 9 eq. (83 mg) iodine in 6 ml dry DMF for 2h. The resin was washed once with DMF and the treatment with 9 eq. (83mg) iodine in 6 ml DMF was repeated. The resin was washed three timeswith 5 ml DMF followed by three times with 5 ml CH₂Cl₂. The peptide wasthen cleaved from the resin, cyclized, deprotected and purified asindicated in procedure B.

HPLC-retention times (minutes) were determined using the gradient method2 as described above: Ex. 154 (3.18), Ex. 155 (3.06).

Purity: %-purity of compounds after prep. HPLC: Ex. 154 (97), Ex. 155(95).

Mass: [M+3H]/3: Ex. 154 (785.4), Ex. 155 (875.4).

Examples 156-157 (n=18) are shown in Table 3. The peptides weresynthesized starting with the amino acid ^(D)Pro which was grafted tothe resin. Starting resin was Fmoc-^(D)ProO-chlorotrityl resin, whichwas prepared as described above. The linear peptides were synthesized onsolid support according to procedure described above in the followingsequence:Resin-^(D)Pro-Gly-P18-P17-P16-P15-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Thereafter the disulfide bridges were formed, and the peptides werecleaved from the resin, cyclized, deprotected and purified as indicatedin procedure B.

HPLC-retention times (minutes) were determined using the gradient method2 as described above: Ex. 156 (3.00), Ex. 157 (2.98).

Purity: %-purity of compounds after prep. HPLC: Ex. 156 (95), Ex. 157(76)

Mass: [M+3H]/3: Ex. 156 (845.5), Ex. 157(848.8)

Examples 158-159 (n=18) are shown in Table 3. The peptides weresynthesized starting with the amino acid Pro which was grafted to theresin. Starting resin was Fmoc-ProO-chlorotrityl resin, which wasprepared as described above. The linear peptides were synthesized onsolid support according to procedure described above in the followingsequence:Resin-Pro-Gly-P18-P17-P16-P15-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Thereafter the disulfide bridges were formed, and the peptides werecleaved from the resin, cyclized, deprotected and purified as indicatedin procedure B.

HPLC-retention times (minutes) were determined using the gradient method2 as described above: Ex. 158 (3.41), Ex. 159 (3.25)

Purity: %-purity of compounds after prep. HPLC: Ex. 158 (95), Ex. 159(83)

Mass: [M+3H]/3: Ex. 158 (848.8), Ex. 159 (822.1).

Examples 160 (n=18) is shown in Table 3. The peptide was synthesizedstarting with the amino acid ^(D)Pro which was grafted to the resin.Starting resin was Fmoc-^(D)ProO-chlorotrityl resin, which was preparedas described above. The linear peptide was synthesized on solid supportaccording to procedure described above in the following sequence:Resin-^(D)Pro-Gly-P18-P17-P16-P15-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Thereafter the following procedure was used:

The peptide (36 μmol) was cleaved from the resin by 1% TFA in CH₂Cl₂After evaporation to dryness 8 ml of dry DMF were added to the tube.Then 2 eq. of HATU in dry DMF (1 ml) and 4 eq. of DIPEA in dry DMF (1ml) were added and stirring was effected for 16 h. The volatiles wereevaporated to dryness. The crude cyclised peptide was dissolved in 7 mlof DCM and extracted with 10% acetonitrile in H₂O (4.5 ml) three times.The organic layer was evaporated to dryness. To deprotect the peptidefully, 3 ml of cleavage cocktail TFA:TIS:H₂O (95:2.5:2.5) was added andkept for 3 h. The volatiles were evaporated to dryness and the crudepeptide was dissolved in 20% acetic acid in water (7 ml) and extractedwith isopropyl ether (4 ml) for three times. The aqueous layer wasdiluted up to 200 ml with water. The pH was adjusted to pH 8 withammonium hydroxide solution. The reaction mixture was shaken for 24 h.The solution was acidified with acetic acid to pH 5, evaporated todryness, and purified by HPLC.

HPLC-retention time (minutes) was determined using the gradient method 2as described above: Ex. 160 (2.92)

Purity: %-purity of compounds after prep. HPLC: Ex. 160 (93)

Mass: [M+3H]/3: Ex. 160 (785.3).

TABLE 1 Examples n = 12 Exam- ple Sequ. ID P1 P2 P3 P4 P5 P6 P7 P8 P9P10 P11 P12 Template Purity %^(a)) (M + 2H)/2 1 SEQ ID Tyr Arg Cit ValArg ^(D)Arg Arg 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 83 1016.1 NO: 1 2SEQ ID Tyr Arg Cit Val Arg ^(D)Arg Arg 2-Nal Val Tyr Cit Lys^(D)Pro^(L)Pro 100 992.4 NO: 2 3 SEQ ID Tyr Arg Cit Phe Arg Arg Arg2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 78 1040.4 NO: 3 4 SEQ ID Tyr ArgCit Val Arg Arg Arg 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 83 1016.7 NO: 45 SEQ ID Tyr Arg Cit Phe Arg Arg Arg 2-Nal Val Tyr Cit Lys^(D)Pro^(L)Pro 89 1016.2 NO: 5 6 SEQ ID Tyr Arg Cit Val Arg Arg Arg2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 100 992.3 NO: 6 7 SEQ ID Tyr ArgCit Cys Arg Arg Arg 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 92 994.8 NO: 78 SEQ ID Tyr Arg Cit Gly Arg Arg Arg 2-Nal Gly Tyr Cit Lys^(D)Pro^(L)Pro 100 1119.3 NO: 8 8 SEQ ID Tyr Arg Cit Ile Arg Arg Arg2-Nal Ile Tyr Cit Lys ^(D)Pro^(L)Pro 100 4.98 NO: 9 10 SEQ ID Tyr ArgCit Thr Arg Arg Arg 2-Nal Thr Tyr Cit Lys ^(D)Pro^(L)Pro 100 993.8 NO:10 11 SEQ ID Tyr Arg Cit Gln Arg Arg Arg 2-Nal Gln Tyr Cit Lys^(D)Pro^(L)Pro 100 1162.0 NO: 11 12 SEQ ID Tyr Arg Cit Cys Arg ^(D)ArgArg 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 100 995.1 NO: 12 13 SEQ ID TyrGly Cit Cys Arg Arg Arg 2-Nal Cys Tyr Gly Lys ^(D)Pro^(L)Pro 64 895.2NO: 13 14 SEQ ID Tyr Arg Cit Cys Arg Arg Arg Trp Cys Tyr Cit Lys^(D)Pro^(L)Pro 87 989.6 NO: 14 ^(a))%-purity of compounds after prep.HPLC Cys in pos. 4 and 9 in Ex. 7, 12-14 form a disulfide bridge

TABLE 2 Examples n = 14 Example Sequ. ID P1 P2 P3 P4 P5 P6 P7 P8 P9 15SEQ ID NO: 15 Tyr Arg Cit Val Arg Val ^(D)Pro Arg Arg 16 SEQ ID NO: 16Tyr Arg Cit Val Arg Val Pro Arg Arg 17 SEQ ID NO 17 Tyr Arg Cit Val ArgPhe ^(D)Pro Arg Arg 18 SEQ ID NO 18 Tyr Arg Cit Val Arg Phe Pro Arg Arg19 SEQ ID NO: 19 Tyr Arg Cit Phe Arg Cit ^(D)Pro Arg Arg 20 SEQ ID NO:20 Tyr Arg Cit Phe Arg Cit Pro Arg Arg 21 SEQ ID NO: 21 Tyr Arg Cit PheArg Val ^(D)Pro Arg Arg 22 SEQ ID NO: 22 Tyr Arg Cit Phe Arg Val Pro ArgArg 23 SEQ ID NO: 23 Tyr Arg Cit Phe Arg Phe ^(D)Pro Arg Arg 24 SEQ IDNO: 24 Tyr Arg Cit Phe Arg Phe Pro Arg Arg 25 SEQ ID NO: 25 Tyr Arg CitVal Arg Cit ^(D)Pro Arg Arg 26 SEQ ID NO: 26 Tyr Arg Cit Val Arg Cit ProArg Arg 27 SEQ ID NO: 27 Tyr Arg Cit Phe Arg Val ^(D)Pro Arg Arg 28 SEQID NO: 28 Tyr Arg Cit Phe Arg Val Pro Arg Arg 29 SEQ ID NO: 29 Tyr ArgCit Phe Arg Phe ^(D)Pro Arg Arg 30 SEQ ID NO: 30 Tyr Arg Cit Phe Arg PhePro Arg Arg 31 SEQ ID NO: 31 Tyr Arg Cit Val Arg Cit Pro Arg Arg 32 SEQID NO: 32 Tyr Arg Cit Val Arg Val ^(D)Pro Arg Arg 33 SEQ ID NO: 33 TyrArg Cit Val Arg Val Pro Arg Arg 34 SEQ ID NO: 34 Tyr Arg Cit Val Arg Phe^(D)Pro Arg Arg 35 SEQ ID NO: 35 Tyr Arg Cit Val Arg Phe Pro Arg Arg 36SEQ ID NO: 36 Tyr Arg Cit Phe Arg Cit ^(D)Pro Arg Arg 37 SEQ ID NO: 37Tyr Arg Cit Phe Arg Cit Pro Arg Arg 38 SEQ ID NO: 38 Tyr Arg Cit Phe ArgGly ^(D)Pro Arg Arg 39 SEQ ID NO: 39 Tyr Arg Cit Phe Arg Gly Gly Arg Arg40 SEQ ID NO: 40 Tyr Arg Cit Phe Arg Val Gly Arg Arg 41 SEQ ID NO: 41Tyr Arg Cit Tyr Arg Pro Val Arg Arg 42 SEQ ID NO: 42 Tyr Arg Cit Tyr ArgPro Val Arg Arg 43 SEQ ID NO: 43 Tyr Arg Cit Tyr Arg Val Gly Arg Arg 44SEQ ID NO: 44 Tyr Arg Cit Val Arg Pro Val Arg Arg 45 SEQ ID NO: 45 TyrArg Cit Val Arg Gly ^(D)Pro Arg Arg 46 SEQ ID NO: 46 Tyr Arg Cit Val ArgGly Gly Arg Arg 47 SEQ ID NO: 47 Tyr Arg Cit Val Arg Val Gly Arg Arg 48SEQ ID NO: 48 Tyr Arg Cit t-BuG Arg Pro Val Arg Arg 49 SEQ ID NO: 49 TyrArg Cit t-BuG Arg Gly Gly Arg Arg 50 SEQ ID NO: 50 Tyr Arg Cit t-BuG ArgVal Gly Arg Arg 51 SEQ ID NO: 51 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg52 SEQ ID NO: 52 Tyr Arg Cit Cys Arg Gly Gly Arg Arg 53 SEQ ID NO: 53Tyr Arg Cit Cys Arg Val Gly Arg Arg 54 SEQ ID NO 54 Tyr Arg Cit Cys ArgGly ^(D)Pro Tyr Arg 55 SEQ ID NO 55 Tyr Arg Cit Cys Arg Gly ^(D)Pro TrpArg 56 SEQ ID NO 56 Tyr Arg Cit Cys Arg Gly ^(D)Pro Thr Arg 57 SEQ. IDNO 57 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 58 SEQ. ID NO 58 Tyr ArgCit Cys Arg Gly ^(D)Pro Arg Arg 59 SEQ. ID NO 59 Tyr Arg Cit Cys Arg Gly^(D)Pro Arg Arg 60 SEQ. ID NO 60 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg61 SEQ. ID NO 61 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 62 SEQ. ID NO62 Gln Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 63 SEQ. ID NO 63 Arg Arg CitCys Arg Gly ^(D)Pro Arg Arg 64 SEQ. ID NO 64 His Arg Cit Cys Arg Gly^(D)Pro Arg Arg 65 SEQ. ID NO 65 Ile Arg Cit Cys Arg Gly ^(D)Pro Arg Arg66 SEQ. ID NO 66 Trp Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 67 SEQ. ID NO67 Thr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 68 SEQ. ID NO 68 Glu Arg CitCys Arg Gly ^(D)Pro Arg Arg 69 SEQ. ID NO 69 Tyr Arg Arg Cys Arg Gly^(D)Pro Arg Arg 70 SEQ. ID NO 70 Tyr Arg His Cys Arg Gly ^(D)Pro Arg Arg71 SEQ. ID NO 71 Tyr Arg Ile Cys Arg Gly ^(D)Pro Arg Arg 72 SEQ. ID NO72 Tyr Arg Tyr Cys Arg Gly ^(D)Pro Arg Arg 73 SEQ. ID NO 73 Tyr Arg TrpCys Arg Gly ^(D)Pro Arg Arg 74 SEQ. ID NO 74 Tyr Arg Pro Cys Arg Gly^(D)Pro Arg Arg 75 SEQ. ID NO 75 Tyr Arg Glu Cys Arg Gly ^(D)Pro Arg Arg76 SEQ. ID NO 76 Tyr Arg Cit Cys Arg Gly ^(D)Pro 4F-Phe Arg 77 SEQ. IDNO 77 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 78 SEQ. ID NO 78 Tyr ArgCit Cys Arg Gly ^(D)Pro Arg Arg 79 SEQ. ID NO 79 Tyr Arg Cit Cys Arg Gly^(D)Pro Arg Arg 80 SEQ. ID NO 80 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg81 SEQ. ID NO 81 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 82 SEQ. ID NO82 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 83 SEQ. ID NO 83 Tyr Arg CitCys Arg Gly ^(D)Pro Arg Arg 84 SEQ. ID NO 84 Tyr Arg Cit Cys Arg Gly^(D)Pro Arg Arg 85 SEQ. ID NO 85 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg86 SEQ. ID NO 86 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 87 SEQ. ID NO87 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 88 SEQ. ID NO 88 Asp Arg CitCys Arg Gly ^(D)Pro Arg Arg 89 SEQ. ID NO 89 Ser Arg Cit Cys Arg Gly^(D)Pro Arg Arg 90 SEQ. ID NO 90 Val Arg Cit Cys Arg Gly ^(D)Pro Arg Arg91 SEQ. ID NO 91 Met Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 92 SEQ. ID NO92 Tyr Arg Asn Cys Arg Gly ^(D)Pro Arg Arg 93 SEQ. ID NO 93 Tyr Arg AspCys Arg Gly ^(D)Pro Arg Arg 94 SEQ. ID NO 94 Tyr Arg Lys Cys Arg Gly^(D)Pro Arg Arg 95 SEQ. ID NO 95 Tyr Arg Ala Cys Arg Gly ^(D)Pro Arg Arg96 SEQ. ID NO 96 Tyr Arg Ser Cys Arg Gly ^(D)Pro Arg Arg 97 SEQ. ID NO97 Tyr Arg Leu Cys Arg Gly ^(D)Pro Arg Arg 98 SEQ. ID NO 98 Tyr Arg ValCys Arg Gly ^(D)Pro Arg Arg 99 SEQ. ID NO 99 Tyr Arg 4F-Phe Cys Arg Gly^(D)Pro Arg Arg 100 SEQ. ID NO 100 Tyr Arg Met Cys Arg Gly ^(D)Pro ArgArg 101 SEQ. ID NO 101 Tyr Arg Cit Cys Ser Gly ^(D)Pro Arg Arg 102 SEQ.ID NO 102 Tyr Arg Ser Cys Arg Gly ^(D)Pro Arg Arg 103 SEQ. ID NO 103 TyrArg Cit Cys Arg Gly ^(D)Pro Arg Arg 104 SEQ. ID NO 104 Tyr Arg Thr CysArg Gly ^(D)Pro Dab Arg 105 SEQ. ID NO 105 Tyr His Cit Cys Arg Gly^(D)Pro Arg Arg 106 SEQ. ID NO 106 Tyr Lys Cit Cys Arg Gly ^(D)Pro ArgArg 107 SEQ. ID NO 107 Phe Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 108 SEQ.ID NO 108 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 109 SEQ. ID NO 109 TyrArg Cit Cys Arg Gly ^(D)Pro Dab Arg 110 SEQ. ID NO 110 Tyr Arg Thr CysArg Gly ^(D)Pro Dab Arg 111 SEQ. ID NO 111 Tyr Arg Cit Cys Dab Gly^(D)Pro Arg Arg 112 SEQ. ID NO 112 Tyr Arg Cit Cys Arg Gly ^(D)Pro ArgArg 113 SEQ. ID NO 113 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 114 SEQ.ID NO 114 Gly Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 115 SEQ. ID NO 115 TyrArg Cit Cys Arg Gly ^(D)Pro Arg Arg 116 SEQ. ID NO 116 Tyr Arg Cit CysArg Gly ^(D)Pro Arg Arg 117 SEQ. ID NO 117 Tyr Arg Cit Cys Arg Gly^(D)Pro Arg Orn 118 SEQ. ID NO 118 Tyr Arg Thr Cys Arg Gly ^(D)Pro 4-PyrAlaArg 119 SEQ. ID NO 119 Tyr 4-PyrAla Thr Cys Arg Gly ^(D)Pro Arg Arg120 SEQ. ID NO 120 Tyr His Thr Cys Arg Gly ^(D)Pro Arg His 121 SEQ. IDNO 121 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 122 SEQ. ID NO 122 TyrArg Cit Cys Arg Gly ^(D)Pro 4F-Phe Arg 123 SEQ. ID NO 123 Tyr Arg CitCys Arg Gly ^(D)Pro Arg Arg 124 SEQ. ID NO 124 Tyr Arg Cit Cys Arg Gly^(D)Pro IsOrn Arg 125 SEQ. ID NO 125 Tyr Arg Cit Cys Arg Gly ^(D)Pro(Im)G Arg 126 SEQ. ID NO 126 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg (Pip)G127 SEQ. ID NO 127 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 128 SEQ. IDNO 128 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 129 SEQ. ID NO 129 TyrArg Cit Cys Arg Gly ^(D)Pro Arg Arg 130 SEQ. ID NO 130 Tyr Arg Gln CysArg Gly ^(D)Pro Arg Arg 131 SEQ. ID NO 131 Tyr Arg Thr Cys Arg Gly^(D)Pro Arg Arg 132 SEQ. ID NO 132 Tyr Arg Cit Cys Arg Gly ^(D)Pro ArgArg 133 SEQ. ID NO 133 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 134 SEQ.ID NO 134 Tyr Arg Cit Cys Arg Gly ^(D)Pro Dab Arg 135 SEQ. ID NO 135 TyrArg Cit Cys Arg Gly ^(D)Pro Dab Arg 136 SEQ. ID NO 136 Tyr Arg Cit CysArg Gly ^(D)Pro Cit Arg 137 SEQ. ID NO 137 Tyr Arg Cit Cys Arg Gly^(D)Pro His Arg 138 SEQ. ID NO 138 Tyr Arg Cit Cys (EA)G Gly ^(D)Pro ArgArg 139 SEQ. ID NO 139 Tyr Arg Cit Cys Arg Gly Pro Arg (EA)G 140 SEQ. IDNO 140 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 141 SEQ. ID NO 141 TyrArg Cit Cys Arg Gly ^(D)Pro Arg Arg 142 SEQ. ID NO 142 Tyr Arg Cit CysArg Gly ^(D)Pro IPeg Dab Arg 143 SEQ. ID NO 143 Tyr Arg Cit Cys Arg Ala^(D)Pro Arg Arg 144 SEQ. ID NO 144 Leu Arg Cit Cys Arg Gly ^(D)Pro ArgArg 145 SEQ. ID NO 145 Tyr Arg Thr Cys Arg Gly ^(D)Pro Arg Arg 146 SEQ.ID NO 146 Tyr Arg Thr Cys Arg Gly ^(D)Pro Arg Arg 147 SEQ. ID NO 147 TyrArg Ile Cys Arg Gly ^(D)Pro Arg Arg 148 SEQ. ID NO 148 Tyr Arg Tyr CysArg Gly ^(D)Pro Arg Arg 149 SEQ. ID NO 149 Tyr Arg Cit Cys Arg Gly^(D)Pro Arg Arg 150 SEQ. ID NO 150 Pip Arg Tyr Cys Tyr Gln Lys ^(D)ProPro 151 SEQ. ID NO 151 Tyr Arg Cit Ser Arg Gly ^(D)Pro Arg Arg 152 SEQ.ID NO 152 Tyr Arg Cit Dab Arg Gly ^(D)Pro Arg Arg 153 SEQ. ID NO 153 TyrArg Cit Glu Arg Gly ^(D)Pro Arg Arg Example P10 P11 P12 P13 P14 TemplatePurity %^(a)) [M + 2H]/2 15 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 1001090.2 16 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 100 1090.4 17 2-Nal ValTyr Cit Lys ^(D)Pro^(L)Pro 100 1114.8 18 2-Nal Val Tyr Cit Lys^(D)Pro^(L)Pro 100 1114.9 19 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 1001143.6 20 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 100 1143.3 21 2-Nal ValTyr Cit Lys ^(D)Pro^(L)Pro 99 1114.3 22 2-Nal Val Tyr Cit Lys^(D)Pro^(L)Pro 100 1114.3 23 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 1001138.1 24 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 100 1138.3 25 2-Nal ValTyr Cit Lys ^(D)Pro^(L)Pro 100 1119.3 26 2-Nal Val Tyr Cit Lys^(D)Pro^(L)Pro 100 1119.3 27 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 1001138.7 28 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 100 1138.3 29 2-Nal PheTyr Cit Lys ^(D)Pro^(L)Pro 100 1162.3 30 2-Nal Phe Tyr Cit Lys^(D)Pro^(L)Pro 100 1219.3 31 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 1001143.3 32 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 100 1114.2 33 2-Nal PheTyr Cit Lys ^(D)Pro^(L)Pro 100 1114.3 34 2-Nal Phe Tyr Cit Lys^(D)Pro^(L)Pro 100 1138.9 35 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 1001138.3 36 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 100 1167.6 37 2-Nal PheTyr Cit Lys ^(D)Pro^(L)Pro 100 1168.2 38 2-Nal Phe Tyr Cit Lys^(D)Pro^(L)Pro 100 1116.8 39 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 1001096.7 40 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 92 1117.6 41 2-Nal TyrTyr Cit Lys ^(D)Pro^(L)Pro 96 1153.8 42 2-Nal Tyr Tyr Cit Lys^(D)Pro^(L)Pro 100 1133.3 43 2-Nal Tyr Tyr Cit Lys ^(D)Pro^(L)Pro 991134.0 44 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 93 1089.7 45 2-Nal ValTyr Cit Lys ^(D)Pro^(L)Pro 100 1068.5 46 2-Nal Val Tyr Cit Lys^(D)Pro^(L)Pro 95 1048.8 47 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 1001070.3 48 2-Nal t-BuG Tyr Cit Lys ^(D)Pro^(L)Pro 98 1103.6 49 2-Nalt-BuG Tyr Cit Lys ^(D)Pro^(L)Pro 93 1062.4 50 2-Nal t-BuG Tyr Cit Lys^(D)Pro^(L)Pro 93 1084.3 51 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 1001071.7 52 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 100 1051.6 53 2-Nal CysTyr Cit Lys ^(D)Pro^(L)Pro 100 1073.2 54 2-Nal Cys Tyr Gln Lys^(D)Pro^(L)Pro 95 1061.4 55 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 951072.9 56 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1030.3 57 2-Nal CysTyr Arg Lys ^(D)Pro^(L)Pro 95 1071.8 58 2-Nal Cys Tyr His Lys^(D)Pro^(L)Pro 95 1061.9 59 2-Nal Cys Tyr Tyr Lys ^(D)Pro^(L)Pro 951075.3 60 2-Nal Cys Tyr Gln Gln ^(D)Pro^(L)Pro 95 1057.8 61 2-Nal CysTyr Gln Glu ^(D)Pro^(L)Pro 95 1058.3 62 2-Nal Cys Tyr Gln Lys^(D)Pro^(L)Pro 95 1040.3 63 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 951054.1 64 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1044.8 65 2-Nal CysTyr Gln Lys ^(D)Pro^(L)Pro 95 1032.9 66 2-Nal Cys Tyr Gln Lys^(D)Pro^(L)Pro 95 1069.2 67 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 951026.7 68 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1040.8 69 2-Nal CysTyr Gln Lys ^(D)Pro^(L)Pro 95 1057.3 70 2-Nal Cys Tyr Gln Lys^(D)Pro^(L)Pro 95 1047.5 71 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 951035.9 72 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1060.9 73 2-Nal CysTyr Gln Lys ^(D)Pro^(L)Pro 95 1072.3 74 2-Nal Cys Tyr Gln Lys^(D)Pro^(L)Pro 95 1027.9 75 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 951043.7 76 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1052.9 77 2-Nal CysTyr Asn Lys ^(D)Pro^(L)Pro 95 1051.1 78 2-Nal Cys Tyr Asp Lys^(D)Pro^(L)Pro 95 1051.4 79 2-Nal Cys Tyr Lys Lys ^(D)Pro^(L)Pro 951057.8 80 2-Nal Cys Tyr Ala Lys ^(D)Pro^(L)Pro 95 1029.4 81 2-Nal CysTyr Ser Lys ^(D)Pro^(L)Pro 95 1037.1 82 2-Nal Cys Tyr Leu Lys^(D)Pro^(L)Pro 95 1050.5 83 2-Nal Cys Tyr Met Lys ^(D)Pro^(L)Pro 951058.9 84 2-Nal Cys Tyr Gln Asn ^(D)Pro^(L)Pro 95 1051.0 85 2-Nal CysTyr Gln Asp ^(D)Pro^(L)Pro 95 1051.4 86 2-Nal Cys Tyr Gln Ala^(D)Pro^(L)Pro 95 1028.9 87 2-Nal Cys Tyr Gln Ser ^(D)Pro^(L)Pro 951037.3 88 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1034.1 89 2-Nal CysTyr Gln Lys ^(D)Pro^(L)Pro 95 1019.8 90 2-Nal Cys Tyr Gln Lys^(D)Pro^(L)Pro 95 1025.8 91 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 951041.3 92 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1036.2 93 2-Nal CysTyr Gln Lys ^(D)Pro^(L)Pro 95 1036.8 94 2-Nal Cys Tyr Gln Lys^(D)Pro^(L)Pro 95 1043.3 95 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 951014.8 96 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1022.8 97 2-Nal CysTyr Gln Lys ^(D)Pro^(L)Pro 95 1035.9 98 2-Nal Cys Tyr Gln Lys^(D)Pro^(L)Pro 95 1028.9 99 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 951052.9 100 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1044.9 101 2-Nal CysTyr Gln Lys ^(D)Pro^(L)Pro 95 1023.3 102 Trp Cys Tyr Cit Asp^(D)Pro^(L)Pro 95 1025.3 103 2-Nal Cys Tyr Cit Glu ^(D)Pro^(L)Pro 951072.7 104 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1001.1 105 Trp CysTyr Cit Lys ^(D)Pro^(L)Pro 95 1056.4 106 Trp Cys Tyr Cit Lys^(D)Pro^(L)Pro 95 1051.5 107 Trp Cys Tyr Cit Lys ^(D)Pro^(L)Pro 951057.5 108 Trp Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1051.0 109 Trp Cys TyrGln Lys ^(D)Pro^(L)Pro 95 1023.0 110 Trp Cys Tyr Gln Lys ^(D)Pro^(L)Pro95 995.0 111 Trp Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1016.9 112 Tyr CysTyr Cit Lys ^(D)Pro^(L)Pro 95 1046.0 113 Tyr Cys Cit Tyr Lys^(D)Pro^(L)Pro 83 1054.0 114 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 951018.0 115 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1057.8 116 Trp CysTyr Cit Lys ^(D)ProA8″-42 68 1153.1 117 Trp Cys Tyr Cit Lys^(D)Pro^(L)Pro 90 1044.5 118 Trp Cys Tyr Gln Lys ^(D)Pro^(L)Pro 951019.0 119 Trp Cys Tyr Gln Lys ^(D)Pro^(L)Pro 90 1019.0 120 Trp Cys TyrGln Lys ^(D)Pro^(L)Pro 95 1013.5 121 Trp Cys Tyr Cit Gln ^(D)Pro^(L)Pro95 1065.5 122 Trp Cys Tyr Cit Lys ^(D)Pro^(L)Pro 95 1070.0 123 Trp CysTyr Cit Lys ^(D)Pro^(L)Pro 95 1065.5 124 2-Nal Cys Tyr Cit Lys^(D)Pro^(L)Pro 95 1106.1 125 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 951075.5 126 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 95 1091.6 127 2-Nal CysTyr Cit NMeK ^(D)Pro^(L)Pro 85 1078.1 128 Trp Cys Tyr Cit Lys^(D)Pro^(L)Pro 93 1066.6 129 2-Nal Cys Tyr NMeGly Lys ^(D)Pro^(L)Pro 891029.1 130 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 79 1057.5 131 2-Nal CysTyr Cit Lys ^(D)Pro^(L)Pro 98 1043.9 132 2-Nal Cys Tyr Thr Lys^(D)Pro^(L)Pro 89 1057.4 133 2-Nal Cys Tyr Thr Lys ^(D)Pro^(L)Pro 901044.0 134 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 88 1044.0 135 2-Nal CysTyr Cit Lys ^(D)Pro^(L)Pro 95 1037.0 136 Trp Cys Tyr Cit Lys^(D)Pro^(L)Pro 95 1066.0 137 Trp Cys Tyr Cit Lys ^(D)Pro^(L)Pro 951056.0 138 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 76 1043.9 139 2-Nal CysTyr Cit Lys ^(D)Pro^(L)Pro 90 1044.0 140 2-Nal Cys Tyr Cit Lys^(D)Pro^(L)Pro 88 1043.9 141 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 951077.1 142 Trp Cys Tyr Cit Lys ^(D)Pro^(L)Pro 95 1117.6 143 Trp Cys TyrCit Lys ^(D)Pro^(L)Pro 95 1072.5 144 2-Nal Cys Tyr Gln Lys^(D)Pro^(L)Pro 87 1032.9 145 Tyr Cys Tyr Gln Lys ^(D)Pro^(L)Pro 951012.6 146 Tyr Cys Tyr Cit Lys ^(D)Pro^(L)Pro 95 1026.6 147 Tyr Cys TyrGln Lys ^(D)Pro^(L)Pro 92 1043.8 148 Tyr Cys Tyr Gln Lys ^(D)Pro^(L)Pro91 1043.8 149 Tyr Cys Tyr Gln Lys ^(D)Gln^(L)Pro 91 1025.7 150 Tyr ArgCit Cys Arg Gly^(D)Pro 95 704.2 151 Trp Asn Tyr Cit Lys ^(D)Pro^(L)Pro67 1065.0 152 Trp Glu Tyr Cit Lys ^(D)Pro^(L)Pro 92 1070.3 153 Trp DabTyr Cit Lys ^(D)Pro^(L)Pro 72 1070.4 Cys in pos. 4 and 11 in Ex. 51-149form a disulfide bridge, Cys in pos. 4 and 13 in Ex. 150 forms adisulfide bridge, Dab resp. Glu in pos. 4 and Glu resp Dab in position11 in Ex. 152 resp. 153 form a lactame bridge, ^(a))%-purity ofcompounds after prep. HPLC

TABLE 3 Examples n = 18 Ex. Sequ. ID P1 P2 P3 P4 P5 P6 P7 P8 P9 154 SEQ.ID NO 154 Arg Arg 2-Nal Cys Tyr Cit Lys Cys Tyr 155 SEQ. ID NO 155 ArgArg Trp Cys Tyr Gln Lys Cys Tyr 156 SEQ. ID NO 156 Arg Arg Trp Cys TyrGln Lys Gly Tyr 157 SEQ. ID NO 157 Arg Arg Trp Cys Tyr Gln Lys Gly Tyr158 SEQ. ID NO 158 Arg Arg Trp Cys Tyr Gln Lys Gly Tyr 159 SEQ. ID NO159 Arg Arg Tyr Cys Tyr Gln Lys Gly Tyr 160 SEQ. ID NO 160 Arg Arg TrpCys Tyr Arg Lys Cys Tyr Ex. P10 P11 P12 P13 P14 P15 P16 P17 P18 Template154 Lys Gly Tyr Cys Tyr Arg Cit Cys Arg Gly^(D)Pro 155 Lys Gly Tyr CysTyr Arg Cit Cys Arg Gly^(D)Pro 156 Lys Gly Tyr Gly Tyr Arg Cit Cys ArgGly^(D)Pro 157 Lys Gly Tyr Gly Tyr Arg Cit Cys Arg Gly^(D)Pro 158^(D)Pro Pro Tyr Gly Tyr Arg Cit Cys Arg Gly^(L)Pro 159 ^(D)Pro Pro TyrGly Tyr Arg Thr Cys Arg Gly^(L)Pro 160 Lys Gly Tyr Cys Tyr Arg Lys CysArg Gly^(D)Pro Cys in pos. 4 and 17 and pos. 8 and 13 in Ex. 154-155 and160 form a disulfide bridge, Cys in pos. 4 and 17 in Ex. 156-159 form adisulfide bridge

2. Biological Methods 2.1. Preparation of the Peptides.

Lyophilized peptides were weighed on a Microbalance (Mettler MT5) anddissolved in sterile water to a final concentration of 1 mM unlessstated otherwise. Stock solutions were kept at +4° C., light protected.

2.2. Ca²⁺⁻ Assay: CXCR4-Antagonizing Activity of the Peptides.

Method 1: 3-4Mio CXCR4 transfected pre-B cells [see references 1, 2 and3, below] per measurement were resuspended in 200 μl MSB (20 mM4-(2-Hydroxyethyl)-piperazin-1-ethanesulfonic acid (HEPES), 136 mM NaCl,4.8 mM KCl and 1 mM CaCl₂) containing 5 mM D-Glucose and were loadedwith 0.75 μl of 1 mM Fura-2-acetoxymethylester (Fura-2-AM) for 17minutes at 37° C. The cells were washed free from Fura-2-AM with aplatelet centrifuge and resuspended in 800 μl MSB containing 5 mMD-Glucose. The peptides to be administered were diluted to a 100 foldend concentration in MSB/0.2% PPL, and 8 pd were injected.[Ca²⁺]_(i)-dependent fluorescence change in response to single orsequential stimulation with the peptide was recorded with a fluorimeterat an excitation wavelength of 340 nM and an end emission wavelength of510 nM [see ref. 4, below]. Measurements were done under continuousstirring at 37° C. The signal intension was calibrated with 3 mM CaCl₂/1mM lonomycin (maximal fura-2-acetoxymethyester saturation) and 10 μMMnCl₂ (minimal Fura-2-acetoxymethylester saturation) and[Ca²⁺]_(i)-changes are presented in % fura-2-acetoxymethylestersaturation. The rate of [Ca²⁺]_(i)-changes was calculated on the basisof the initial [Ca²⁺]_(i)-changes and plotted in dependence of chemokineconcentration to obtain a sigmoidal curve and to determine the IC₅₀values.

MSB: 20 mM HEPES, 136 mM NaCl, 4.8 mM KCl, 1 mM CaCl₂.2H₂O, pH 7.4;

Osmolarity: 310 mOsm adjusted with NaOH or HCl, adjusted with H₂O orPBS.

MSB plus; 5 mM D-glucose in MSB (50 mg/50 mL).

Fura 2-acetoxymethylester: 1 mM stock solution in dimethulsulfoxide.

Method 2: Increases in intracellular calcium were monitored using aFlexstation 384 (Molecular Devices, Sunnyvale Calif.) to assay thepeptides for CXCR4 antagonism in a mouse pre-B cell line 300-19 stablytransfected with human CXCR4 [see references 1, 2 and 3, below]. Thecells were batch loaded with the Calcium 3 Assay kit (Molecular Devices)in assay buffer (Hanks Balanced salt solution, HBSS, 20 mM HEPES, pH7.4, 0.1% BSA) for 1 h at room temperature and then 200,000 labeledcells were dispensed into black 96 well assays plates (Costar No. 3603).A 20-fold concentrated solution of peptide in assay buffer was added tothe cells and the whole plate was centrifuged to settle the cells to thebottom of the wells. Calcium mobilization induced by 10 nMstromal-derived factor-1 (SDF-1) was measured in the Flexstation 384(excitation, 485 nM; emission, 525 nM) for 90 seconds. A maximal changein fluorescence response above baseline was used to calculate antagonistactivity. The data for dose response curves (antagonist concentrationversus % maximum response) were fitted to a four parameter logisticequation using SoftmaxPro 4.6 (Molecular Devices), from which IC₅,values were calculated.

2.3. FIGS-Assay™

The assay was performed according to ref. 5, below. Stock dilutions ofthe peptides (10 mM) were prepared by dissolving in 10 mM Tris-HCl atroom temperature. Stock solutions were kept at +4° C., light protected.Working dilution were prepared extemporaneously by serial dilution inPhosphate Buffered Saline(PBS) and added in a final volume of 10 μldirectly to the cell cultures. After 48 hours of co-cultivation thecultures were rinsed with PBS and then exposed toglutaraldehyde/formaldehyde (0.2%/2%) in PBS for five minutes. Forphotometric quantification the fixed cultures were subsequentlyincubated with ortho-nitro-phenyl-galactopyranoside (ONPG) as aβ-galactosidase substrate, which was enzymatically converted into thechromophore ortho-nitrophenol (ONP). The read out is directly obtainedby measuring optical density of wells at 405 nm in an iEMS 96well-platereader.

2.4. Cytotoxicity Assay

The cytotoxicity of the peptides to HELA cells (Acc57) and COS-7 cells(CRL-1651) was determined using the MTT reduction assay [see ref. 6 and7, below]. Briefly the method was as follows: HELA cells and COS-7 cellswere seeded at 7.0′10³ and, respectively, 4.5′10³ cells per well andgrown in 96-well microtiter plates for 24 hours at 37° C. at 5% CO₂. Atthis point, time zero (Tz) was determined by MTT reduction (see below).The supernatant of the remaining wells was discarded, and fresh mediumand the peptides in serial dilutions of 12.5, 25 and 50 μM were pipettedinto the wells. Each peptide concentration was assayed in triplicate.Incubation of the cells was continued for 48 hours at 37° C. at 5% CO₂.Wells were then washed once with PBS and subsequently 100 μl MTT reagent(0.5 mg/mL in medium RPMI1640 and, respectively, DMEM) was added to thewells. This was incubated at 37° C. for 2 hours and subsequently themedium was aspirated and 100 μl isopropanol was added to each well. Theabsorbance at 595 nm of the solubilized product was measured(OD₅₉₅peptide). For each concentration averages were calculated fromtriplicates. The percentage of growth was calculated as follows:(OD₅₉₅peptide-OD₅₉₅Tz-ODs₅₉₅Empty well)/(OD₅₉₅Tz-OD₅₉₅Empty well)×100%and was plotted for each peptide concentration.

The LC 50 values (Lethal. Concentration, defined as the concentrationthat kills 50% of the cells) were determined for each peptide by usingthe trend line function of EXCEL (Microsoft Office 2000) for theconcentrations (50, 25, 12.5 and 0 μM), the corresponding growthpercentages and the value −50, (=TREND(C50:C0,%50:%0,−50)). The GI 50(Growth Inhibition) concentrations were calculated for each peptide byusing a trend line function for the concentrations (50, 25, 12.5 and 0μg/ml), the corresponding percentages and the value 50, (=TREND(C₅₀:C₀,%₅₀:%₀,50).

2.5. Cell Culture

‘CCR5’ cells were cultured in DMEM medium with 4500 mg/ml glucose, 10%fetal bovine serum (FBS), supplemented with 50 U/ml Penicillin and 50Ag/ml Streptomycin (Pen/Strept.). Hut/4-3 cells were maintained in RPMImedium, 10% FBS, supplemented with Pen/Strept. and 10 mM HEPES. HELAcells and CCRF-CEM cells were maintained in RPM 11640 plus 5% FBS,Pen/Strept and 2 mM L-Glutamine. Cos-7 cells were grown in DMEM mediumwith 4500 mg/ml glucose supplemented with 10% FCS, Pen/Strept. and 2 mML-Glutamine. All cell lines were grown at 37° C. at 5% CO₂. Cell media,media supplements, PBS-buffer, HEPES, Pen/Strept, L-Glutamine and serawere purchased from Gibco (Pailsey. UK). All fine chemicals came fromMerck (Darmstadt, Germany).

2.6. Hemolysis

The peptides were tested for their hemolytic activity against human redblood cells (hRBC). Fresh hRBC were washed three times with phosphatebuffered saline (PBS) by centrifugation for 10 min at 2000×g. Peptidesat a concentration of 100 μM were incubated with 20% v/v hRBC for 1 hourat 37° C. The final erythrocyte concentration was approximately 0.9×10⁹cells per ml. A value of 0% resp. 100% cell lysis was determined byincubation of the hRBC in the presence of PBS alone and respectively0.1% Triton X-100 in H₂O. The samples were centrifuged and thesupernatant was 20-fold diluted in PBS buffer and the optical density(OD) of the sample at 540 nM was measured. The 100% lyses value(OD₅₄₀H₂O) gave an OD₅₄₀ of approximately 1.3-1.8. Percent hemolysis wascalculated as follows: (OD₅₄₀peptide/OD₅₄₀H₂O)×100%.

2.7. Chemotactic Assay (Cell Migration Assay)

The chemotactic response of CCRF-CEM cells to a gradient of stromalcell-derived factor 1α SDF-1) was measured using disposable assay platesfrom Neuroprobe (5 ppore size) (Gaithersburg, Md.), according to themanufacturer's directions and references therein [especially ref. 8,below]. Briefly, one 175 cm² flask was washed once with Dubecco'sphosphate buffered saline (DPBS), and trypsinized for 10 minutes oruntil cells had lifted. The trypsin was neutralized by the addition offresh medium containing serum and the cells were pelleted, washed oncein DPBS, and resuspended at 1-0.5×10⁷ cells/ml in RPMI+0.5% bovine serumalbumin (BSA). 45 μl of cell suspension were mixed with 5 μl of 10-foldconcentrated PEM peptide diluted in the same assay medium. 35 μl of thismixture were applied to the top of the assay filter. The cells wereallowed to migrate (at 370) into the bottom chamber of the assay platecontaining 1 nM SDF-1. After 4 hours, the filter was removed and MTT wasadded to the migrated cells to a final concentration of 0.5 mg/ml, andincubated for a further 4 hours. After labeling with MTT, all medium wasremoved and 100 μl of isopropanol+10 mM HCl were added to the cells. Theoptical absorbance at 595 nm (ABS₅₉₅) was read using a Tecan Geniosplate reader with Magellan software. The number of cells migrated wasdetermined by comparing ABS₅₉₅ values against a standard curve generatedwith a known number of cells in the assay plate and were plotted againstSDF-1 concentration to obtain a sigmoidal curve and to determine theIC₅₀ values. The values for IC50 were determined using the Trendlinefunction in Microsoft Excel by fitting a logarithmic curve to theaveraged datapoints.

2.8 Plasmastability

405 μl of plasma/albumin solution were placed in a polypropylene (PP)tube and spiked with 45 μl of compound from a 100 μM solution B, derivedfrom 135 μl of PBS and 15 μl of 1 mM peptide in PBS, pH 7.4. 150 μlaliquots were transferred into individual wells of the 10 kDa filterplate (Millipore MAPPB 1010 Biomax membrane). For “0 minutes controls”:270 μl of PBS were placed in a PP tube and 30 μl of stock solution B wasadded and vortexed. 150 μl of control solution was placed into one wellof the filter plate and serves as “filtered control”. Further 150 μl ofcontrol solution were placed directly into a receiver well (reserved forfiltrate) and serve as “not-filtered control”. The entire plateincluding evaporation lid was incubated for 60 min at 37° C. Plasmasamples (rat plasma: Harlan Sera lab UK, human plasma: BlutspendezentrumZüirich) were centrifuged at least for 2 h at 4300 rpm (3500 g) and 15°C. in order to yield 100 μl filtrate. For “serum albumin”-samples(freshly prepared human albumin: Sigma A-4327, rat albumin: SigmaA-6272, all at 40 mg/ml concentration in PBS) approximately 1 hour ofcentrifugation is sufficient. The filtrates in the receiver PP platewere analysed by LC/MS as follows: Column: Jupiter C18 (Phenomenex),mobile phases: (A) 0.1% formic acid in water and (B) acetonitrile,gradient: 5%-100% (B) in 2 minutes, electrospray ionization, MRMdetection (triple quadrupole). The peak areas were determined andtriplicate values are averaged. The binding is expressed in percent ofthe (filtered and not-filtered time point 0 min) control 1 and 2 by:100−(100*T₆₀/T₀). The average from these values is then calculated (seeref. 9 below).

2.9. Pharmacokinetic Study (PK)

Pharmacokinetic study after single intravenous (i.v.) andintraperitoneal (i.p.) administration was performed for the compound ofExample 51 (“Ex. 51”). 30 grams (±20%) male CD-1 mice obtained fromCharles River Laboratories Deutschland GmbH were used in the study. Thevehicle, physiological saline, was added to give a final concentrationof 1 mg/ml of the compounds. The volume was 2 ml/kg i.v. and 10 ml/kgi.p and the peptide Ex. 51 was injected to give a final intraperitonealdose of 10 mg/kg and an intravenous dose of 2 mg/kg. Approximately250-300 μl of blood was removed under light isoflurane anesthesia fromthe retro-orbital plexus at predetermined time intervals (0, 5, 15, 30min and 1, 2 and 3 hours for the i.v. study and 0, 15, 30 min and 1, 2,4 and 8 hours for the i.p. study) and added to heparinized tubes. Plasmawas removed from pelleted cells upon centrifugation and frozen at −80°C. prior to HPLC-MS analysis.

Preparation of the Plasma Calibration Samples “Blank” mouse plasma fromuntreated animals was used. Aliquots of plasma of 0.2 ml each werespiked with 50 ng of propranolol (Internal Standard, IS), (samplepreparation by solid phase extraction on OASIS® HLB cartridges (Waters))and with known amounts of Ex. 51 in order to obtain 9 plasma calibrationsamples in the range 10-5000 nM. The OASIS® HLB cartridges wereconditioned with 1 ml of methanol and then with 1 ml of 1% NH₃ in water.Samples were then diluted with 700 μl of 1% NH₃ in water and loaded.

The plate was washed with 1 ml of methanol/1% NH₃ in water 5/95. Elutionwas performed using 1 ml of 0.1% TFA in methanol.

The plate containing eluates was introduced into the concentrator systemand taken to dryness.

The residues were dissolved in 100 μL of formic acid 0.1%/acetonitrile,95/5 (v/v) and analysed in the HPLC/MS on a reverse phase analyticalcolumn (Jupiter C 18, 50×2.0 mm, 5 μm, Phenomenex), using gradientelution (mobile phases A: 0.1% formic acid in water, B: Acetonitrile;from 5% B to 100% B in 2 min.).

Preparation of Plasma Samples

Samples coming from animal treatments were pooled in order to obtain anappropriate volume for the extraction. If the total volume obtained wasless than 0.2 ml the appropriate amount of “blank” mouse plasma wasadded in order to keep the matrix identical to the calibration curve.Samples were than spiked with IS and processed as described for thecalibration curve.

Pharmacokinetic Evaluation

PK analysis was performed on pooled data (generally n=2 or 3) using thesoftware PK solutions 2.0™ (Summit Research Service, Montrose, Colo.81401 USA). The area under the curve AUC was calculated by the lineartrapezoidal rule. AUC_((t-∞)) was estimated as Ct/b (b: elimination rateconstant). AUC_((t-∞)) is the sum of AUC_((0-t)) and AUC_((t-∞)).Elimination half-life was calculated by the linear regression on atleast three data points during the elimination phase. The time intervalsselected for the half-life determinations were evaluated by thecorrelation coefficient (r²), which should be at least above 0.85 andmost optimally above 0.96. In case of i.v. administration the initialconcentration at t_(zero) was determined by extrapolation of the curvethrough the first two time points. Finally bioavailability after i.p.administration was calculated from the normalised AUC_((0-∞)) rationafter i.p. versus i.v. administration.

3.0. Results

The results of the experiments described under 2.2-2.7, above, areindicated in Table 4 herein below.

TABLE 4 Cyto- IC₅₀ (μM) FIGS ™ toxicity Hemo- Cell IC₅₀ (nM) %inhibition St. dev. LC₅₀/GI₅₀ lysis at migration Ex. Ca²⁺ assay at 200nM at 200 nM Hela cells 100 μM assay 1 2280 n.d. n.d. 82 1.6 n.d. 2 2830n.d. n.d. 97 0.9 n.d. 3 1000 n.d. n.d. 126 1.7 n.d. 4 2540 n.d. n.d. 1910.7 n.d. 6 1930 n.d. n.d. 103 0.6 n.d. 20 3730 n.d. n.d. 85 0.2 n.d. 21550 n.d. n.d. 114 0.6 n.d. 22 300 n.d. n.d. 139 0.0 n.d. 23 1550 n.d.n.d. 49 1.4 n.d. 24 850 n.d. n.d. 108 0.7 n.d. 25 1000 n.d. n.d. 108 0.0n.d. 28 2680 n.d. n.d. 117 0.9 n.d. 31 1470 n.d. n.d. 82 0.1 n.d. 32 760n.d. n.d. 85 0.5 n.d. 38 719.7 n.d. n.d. 348 0.3 n.d. 45 n.d. 65.1 4.8132 0.4 n.d. 51 1.7 93.9 1.0 97 0.0  0.275 52 3.1 95.4 1.3 99 0.0 2.7553 57.8 91.8 1.6 86 0.2 n.d. 54 6.9 n.d. n.d. 54 0.0 n.d. 55 6.3 n.d.n.d. 43 0.1 n.d. 56 0.74 n.d. n.d. 60 — n.d. 57 4.2 n.d. n.d. 33 0.1n.d. 58 10.5 n.d. n.d. 18 0.0 n.d. 59 7.8 n.d. n.d. 33 0.1 n.d. 60 0.18n.d. n.d. 62 0.1 n.d. 61 4.1 n.d. n.d. >100 0.3 n.d. 62 1.8 n.d. n.d. 650.1 n.d. 63 2.0 n.d. n.d. 58 0.2 n.d. 64 3.3 n.d. n.d. 66 0.3 n.d. 653.9 n.d. n.d. 65 0.2 n.d. 66 3.8 n.d. n.d. 46 0.0 n.d. 67 2.4 n.d. n.d.49 0.2 n.d. 68 1.1 n.d. n.d. >100 0.1 n.d. 69 1.8 n.d. n.d. 49 0.1 n.d.70 19.5 n.d. n.d. 40 0.2 n.d. 71 2.7 n.d. n.d. 34 0.1 n.d. 72 3.9 n.d.n.d. 36 0.5 n.d. 73 8.8 n.d. n.d. 20 0.3 n.d. 74 19.5 n.d. n.d. 40 0.4n.d. 75 3.5 n.d. n.d. >100 0.0 n.d. 76 5.6 n.d. n.d. >100 0.1 n.d. 77 7n.d. n.d. >100 0.2 n.d. 78 11 n.d. n.d. 69 0.1 n.d. 79 2.4 n.d. n.d. 940.0 n.d. 80 2.9 n.d. n.d. 44 0.1 n.d. 81 4.9 n.d. n.d. 45 0.0 n.d. 824.8 n.d. n.d. 40 0.0 n.d. 83 3.7 n.d. n.d. 48 0.1 n.d. 84 3.9 n.d. n.d.62 0.0 n.d. 85 2.7 n.d. n.d. 94 0.0 n.d. 86 0.69 n.d. n.d. 62 0.0 n.d.87 3.5 n.d. n.d. 64 0.0 n.d. 88 2.5 n.d. n.d. 44 0.0 n.d. 89 0.5 n.d.n.d. 50 0.0 n.d. 90 19.5 n.d. n.d. 57 0.1 n.d. 91 2.1 n.d. n.d. 48 0.2n.d. 92 1.1 n.d. n.d. 53 0.5 n.d. 93 4.3 n.d. n.d. >100 0.2 n.d. Cyto-IC₅₀ (μM) FIGS ™ toxicity Hemo- Cell IC₅₀ (nM) % inhibition St. dev.GI₅₀ lysis at migration Ex. Ca²⁺ assay at 200 nM at 200 nM Hela cells100 μM assay 94 2.5 n.d. n.d. 45 0.2 n.d. 95 2.9 n.d. n.d. 41 0.1 n.d.96 3.0 n.d. n.d. 69 1.0 n.d. 97 4.3 n.d. n.d. 44 0.8 n.d. 98 3.9 n.d.n.d. 41 1.0 n.d. 99 4.2 n.d. n.d. 40 1.1 n.d. 100 7.0 n.d. n.d. 43 0.8n.d. 101 1.28 n.d. n.d. 74 0.6 n.d. 102 8.0 n.d. n.d. 33 0.5 n.d. 10318.3 n.d. n.d. 42 0.2 n.d. 104 7.4 n.d. n.d. 71 0.0 n.d. 105 0.62 n.d.n.d. 49 0.0 n.d. 106 3.1 n.d. n.d. 83 0.0 n.d. 107 3.8 n.d. n.d. 50 0.4n.d. 108 4.6 n.d. n.d. 70 0.0 n.d. 109 3.0 n.d. n.d. 65 0.0 n.d. 110 1.7n.d. n.d. 48 0.0 n.d. 111 1.6 n.d. n.d. >100 0.0 n.d. 112 7.8 n.d. n.d.76 0.0 n.d. 113 0.62 n.d. n.d. 45 0.0 n.d. 114 1.3 n.d. n.d. 67 0.0 n.d.115 2.7 n.d. n.d. >100 0.1 n.d. 116 14.5 n.d. n.d. 20 0.0 n.d. 117 3.4n.d. n.d. 44 0.0 n.d. 118 7.6 n.d. n.d. 52 0.0 n.d. 119 9.4 n.d. n.d. 630.0 n.d. 120 8.1 n.d. n.d. 78 0.0 n.d. 121 6.5 n.d. n.d. 79 0.0 n.d. 1228.8 n.d. n.d. 60 0.0 n.d. 123 10.0 n.d. n.d. 80 0.0 n.d. 124 5.9 n.d.n.d. 21 0.0 n.d. 125 330.0 n.d. n.d. >100 0.0 n.d. 126 19.5 n.d. n.d. 850.0 n.d. 127 52.2 n.d. n.d. 62 0.0 n.d. 128 4.5 n.d. n.d. 43 0.0 n.d.129 10.9 n.d. n.d. 23 0.0 n.d. 130 4.1 n.d. n.d. 62 0.0 n.d. 131 2.4n.d. n.d. 53 0.0 n.d. 132 1.9 n.d. n.d. 76 0.0 n.d. 133 5.3 n.d. n.d. 450.1 n.d. 134 1.7 n.d. n.d. 21 0.0 n.d. 135 4.7 n.d. n.d. 30 0.1 n.d. 1364.1 n.d. n.d. >100 0.0 n.d. 137 1.28 n.d. n.d. 79 0.5 n.d. 138 63.0 n.d.n.d. 18 0.0 n.d. 140 19.6 n.d. n.d. 35 0.0 n.d. 141 >10 n.d. n.d. 18n.d. n.d. 142 96.9 n.d. n.d. n.d. n.d. n.d. 143 0.9 n.d. n.d. 46 n.d.n.d. 144 0.18 n.d. n.d. n.d. n.d. n.d. 145 0.38 n.d. n.d. 97 0.0 n.d.146 0.24 n.d. n.d. n.d. n.d. n.d. 147 0.17 n.d. n.d. n.d. n.d. n.d. 1480.65 n.d. n.d. 46 71   n.d. 149 1.0 n.d. n.d. >100 0.0 n.d. 150 1.4 n.d.n.d. n.d. n.d. n.d. 151 4.2 n.d. n.d. 83 0.9 n.d. 152 4.2 n.d. n.d. 460.0 n.d. 153 21.9 n.d. n.d. 43 1.7 n.d. 154 9.3 n.d. n.d. n.d. n.d. n.d.155 0.46 n.d. n.d. n.d. n.d. n.d. 156 49 n.d. n.d. n.d. n.d. n.d. 15711.3 n.d. n.d. n.d. n.d. n.d. 158 250 n.d. n.d. n.d. n.d. n.d. 159 118n.d. n.d. n.d. n.d. n.d. 160 0.38 n.d. n.d. n.d. n.d. n.d. n.d.: notdetermined

The determination of IC₅₀ (nM) values in the Ca²⁺ assay for Ex. 1-53 wasperformed using method 1, for Ex. 54-155 method 2 was used. For thedetermination of cytotoxicity values in Ex. 1-53 the IC₅₀ calculationwas used, for Ex. 52-160 the GI₅₀ calculation was used.

The determination of IC50 (nM) values in the Ca²⁺ assay for Ex. 1-53 wasperformed using method 1, for Ex. 54-160 method 2 was used.

The determination of IC50 (nM) values in the Ca2+ assay for Ex. 1-53 wasperformed using method 1, for Ex. 54-155 method 2 was used. For thedetermination of cytotoxicity values in Ex. 1-53 the LC50 calculationwas used, for Ex. 52-160 the GI50 calculation was used.

The determination of IC50 (nM) values in the Ca2+ assay for Ex. 1-53 wasperformed using method 1, for Ex. 54-160 method 2 was used.

The results of the experiment described in 2.8, above, are indicated inTable 5 herein below.

TABLE 5 Ex. Stability human Plasma t_(1/2) (min) Stability rat Plasmat_(1/2) (min) 51 286 >300 60 >300 >300 61 273 >300 68 127 81 75 188 14285 166 >300 101 >300 247 102 255 245 110 115 259 124 >300 >300 120 39174 151 89 71 152 23 86

The results of the experiment described in 2.9 (PK), above, areindicated in Tables 6, 7 and 8 herein below.

TABLE 6 Route i.v. Dose 2 mg/kg n. of Time Calc. Conc animals (h.)(ng/ml) pooled 0.083 1461 3 0.25 328 2 0.5 300 3 1 80 3 2 68 3 3 49 3

TABLE 7 Route i.p. Dose 10 mg/kg n. of Time Calc. Conc animals (h.)(ng/ml) pooled 0.25 673 3 0.5 1568 2 1 2009 2 2 3160 2 4 1024 3 8 519 3

TABLE 8 Administration route Intravenous Intraperitoneal Dose (mg/kg) 210 AUC_(o-t) (ng · h/ml 1704 11112 AUC_(o-inf.) (ng · h/ml) 1905 12948AUC_(norm.) (ng · h/ml) 953 1295 C_(max) ng/ml 28594 3160 C_(max norm.)14297 316 T_(max) (hour) 0 2 β (hours⁻¹) 0.24 0.28 Half-life (hours) 2.82.5 % absorbed (F) (percentage of 100 136 normalized AUC_(o-inf)intraperitoneal against normalized AUC_(o-inf) i.v.)

After intravenous administration of Ex. 51 at a dose level of 2 mg/kgbody weight. Ex. 51 followed intravenous kinetic characteristics. AfterPK analysis, Ex. 51 showed an extrapolated C_(initial) of 28594 ng/mland a C_(max) observed of 1461 ng/ml at 5 min. Plasma levels rapidlydecreased to 328 and 80 ng/ml at 15 min and 1 hour respectively. From 1to 3 h plasma levels decreased with an elimination half-life of 2.8 h to49 ng/ml at 3 h.

The AUC_((0-t)) and AUC_((0-∞)) amounted to 1704 and 1905 ng·h/ml,respectively. After intraperitoneal administration of Ex. 51 at a doselevel of 10 mg/kg body weight, plasma levels of Ex. 51 increased almostlinearly within the first 2 h and showed a C_(max) of 3160 ng/ml at 2hours. From 2 to 8 h plasma levels decreased with an eliminationhalf-life of 2.5 h to 519 ng/ml at 8 h. The AUC_((0-t)) and AUC_((0-∞))amounted to 11112 and 12948 ng·h/ml, respectively. As compared to thenormalized AUC value after i.v. administration (100% absorbed, 953ng·h/ml) of Ex. 51 absorbed after i.p. administration amounted to 136%(1295 ng·h/ml) at an 45 times lower normalised Cmaxafter i.p.administration (316 versus 1497 ng/ml). The value above 100% maypartially reflect an impaired reliability caused by the limited numberof points.

REFERENCES

-   1. Oberlin E, Amara A, Bachelerie F, Bessia C, Virelizier J-L,    Arenzana-Seisdedos F, Schwartz O, Heard J-M, Clark-Lewis I,    Legler D. F., Loetscher M, Baggiolini M, Moser B. Nature, 1996,    382:833-835-   2. Loetscher M, Geiser T, O'Reilly T, Zwalen R, Baggiolini M,    Moser B. J. Biol. Chem. 1994. 269:232-237-   3. D'Apuuo M, Rolink A, Loetscher M, Hoxie J. A., Clark-Lewis I,.    Melchors F, Baggiolini M, Moser B. Eur. J. Immunol. 1997.    27:1788-1793-   4. von Tscharner V, Prod'hom B, Baggiolini M, Reuter H.    Nature. 1986. 324:369-72.-   5. Hamy F, Felder E. R., Heizmann G, Lazdins J, Aboul-ela F, Varani    G, Karn J, Klimkait T. Proc. Natl. Acad. Sci. 1997. 94:3548-3553.-   6. Mossman T. J. Immunol. Meth. 1983, 65:55-63-   7. Berridge M. V., Tan A. S. Arch. Biochem. Biophys. 1993,    303:474-482-   8. Frevert C. W., Wong V. A., Goodman R. V., Goodwin R, Martin T.    R., J. Immunol. Meth. 1998.213: 41-52-   9. Singh R., Chang, S. Y., Talor, L. C., Rapid Commun. Mass    Spectrom., 1996, 10: 1019-1026

1. A compound of the general formula

is a group of one of the formulae

is Gly or the residue of an L-α-amino acid with B being a residue offormula —NR²⁰CH(R⁷¹)— or the enantiomer of one of the groups A1 to A69as defined hereinafter;

is a group of one of the formulae

R¹ is H; lower alkyl; or aryl-lower alkyl; R² is H; alkyl; alkenyl;—(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R³ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R⁴ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(p)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R⁵ isalkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R⁶ is H;alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R⁷ isalkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(r)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(r)(CHR⁶¹)_(s) C₆H₄R⁸; R⁸ is H; Cl; F; CF₃; NO₂; lower alkyl;lower alkenyl; aryl; aryl-lower alkyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)NR³³R³⁴;—(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)COR⁶⁴; R⁹ is alkyl; alkenyl;—(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R¹⁰ isalkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶)₂;—(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R¹¹ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹), C₆H₄R⁸; R¹² is H; alkyl; alkenyl;—(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(r)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸; R¹³ isalkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(q)(CHR⁶¹)_(s)SR⁵⁶;(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(q)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸; R¹⁴ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(q)(CHR⁶¹)_(s)SOR⁶²; or—(CH₂)_(q)(CHR⁶¹)_(s) C₆H₄R⁸; R¹⁵ is alkyl; alkenyl;—(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R¹⁶ isalkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R¹⁷ isalkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(q)(CHR⁶¹)_(s)SR⁵⁶;(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(q)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸; R¹⁸ isalkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(p)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R¹⁹ islower alkyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(p)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; or R¹⁸ andR¹⁹ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; R²⁰ is H; alkyl; alkenyl; oraryl-lower alkyl; R²¹ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R²² is H; alkyl; alkenyl;—(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R²³ isalkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R²⁴ isalkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R²⁵ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R²⁶ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; or R²⁵ andR²⁶ taken together can form: —(CH₂)₂₋₆—; —(CH₂)_(r)O(CH₂)_(r)—;—(CH₂)_(r)S(CH₂)_(r)—; or —(CH₂)_(r)NR⁵⁷(CH₂)_(r); R²⁷ is H; alkyl;alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R²⁸ isalkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹), —OR⁵⁵; —(CH₂)_(o)(CHR⁶¹), SR⁵⁶;—(CH₂)_(o)(CHR⁶¹), NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹), COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹), CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s) PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹), C₆H₄R⁸; R²⁹ isalkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R³⁰ is H;alkyl; alkenyl; or aryl-lower alkyl; R³¹ is H; alkyl; alkenyl;—(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹), C₆H₄R⁸; R³² is H; lower alkyl; or aryl-lower alkyl;R³³ is H; alkyl, alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COR⁶⁴;—(CH₂)_(o)(CHR⁶¹), —CONR⁵⁸R⁵⁹, —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R³⁴ is H;lower alkyl; aryl, or aryl-lower alkyl; R³³ and R³⁴ taken together canform: —(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; R³⁵ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹), C₆H₄R⁸; R³⁶ is H,alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹), C₆H₄R⁸; R³⁷ is H; F; Br; Cl; NO₂; CF₃; lower alkyl;—(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹), C₆H₄R⁸; R³⁸ is H; F; Br; Cl; NO₂; CF₃; alkyl;alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R³⁹ is H; alkyl; alkenyl; or aryl-loweralkyl; R⁴⁰ is H; alkyl; alkenyl; or aryl-lower alkyl; R⁴¹ is H; F; Br;Cl; NO₂; CF₃; alkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s) C₆H₄R⁸; R⁴² is H;F; Br; Cl; NO₂; CF₃; alkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s) C₆H₄R⁸; R⁴³ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s) C₆H₄R⁸; R⁴⁴ is alkyl; alkenyl;—(CH₂)_(r)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(r)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(r)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(r)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(r)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(r)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸; R⁴⁵ is H;alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(s)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(s)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(s)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(s)(CHR⁶¹)_(s)C₆H₄R⁸; R⁴⁶ is H;alkyl; alkenyl; or —(CH₂)_(o)(CHR⁶¹)_(p)C₆H₄R⁸; R⁴⁷ is H; alkyl;alkenyl; or —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; R⁴⁸ is H; lower alkyl; loweralkenyl; or aryl-lower alkyl; R⁴⁹ is H; alkyl; alkenyl;—(CHR⁶¹)_(s)COOR⁵⁷; (CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; (CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CHR⁶¹)_(s)SOR⁶²; or —(CHR⁶¹)_(s)C₆H₄R⁸; R⁵⁰ is H; lower alkyl; oraryl-lower alkyl; R⁵¹ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s) SO₂R⁶²; or—(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸; R⁵² is H; alkyl; alkenyl;—(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂;—(CH₂)_(p)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸; R⁵³ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂;—(CH₂)_(p)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸; R⁵⁴ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; or—(CH₂)_(o)(CHR⁶¹), C₆H₄R⁸; R⁵⁵ is H; lower alkyl; lower alkenyl;aryl-lower alkyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁷;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)(CHR⁶¹), —COR⁶⁴;—(CH₂)_(o)(CHR⁶¹)COOR⁵⁷; or —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; R⁵⁶ is H;lower alkyl; lower alkenyl; aryl-lower alkyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁷;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)(CHR⁶¹), —COR⁶⁴; or—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; R⁵⁷ is H; lower alkyl; lower alkenyl;aryl lower alkyl; or heteroaryl lower alkyl; R⁵⁸ is H; lower alkyl;lower alkenyl; aryl; heteroaryl; aryl-lower alkyl; or heteroaryl-loweralkyl; R⁵⁹ is H; lower alkyl; lower alkenyl; aryl; heteroaryl;aryl-lower alkyl; or heteroaryl-lower alkyl; or R⁵⁸ and R⁵⁹ takentogether can form: —(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; R⁶⁰ is H; lower alkyl; lower alkenyl; aryl; oraryl-lower alkyl; R⁶¹ is alkyl; alkenyl; aryl; heteroaryl; aryl-loweralkyl; heteroaryl-lower alkyl; —(CH₂)_(m)OR⁵⁵; —(CH₂)_(m)NR³³R³⁴;—(CH₂)_(m)OCONR⁷⁵R⁸²; —(CH₂)_(m)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)COOR³⁷;—(CH₂)_(o)NR⁵⁸R⁵⁹; or —(CH₂)_(o)PO(COR⁶⁰)₂; R⁶² is lower alkyl; loweralkenyl; aryl, heteroaryl; or aryl-lower alkyl; R⁶³ is H; lower alkyl;lower alkenyl; aryl, heteroaryl; aryl-lower alkyl; heteroaryl-loweralkyl; —COR⁶⁴; —COOR⁵⁷; —CONR⁵⁸R⁵⁹; —SO₂R⁶²; or —PO(OR⁶⁰)₂; R³⁴ and R⁶³taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—;or —(CH₂)₂NR⁵⁷(CH₂)₂—; R⁶⁴ is H; lower alkyl; lower alkenyl; aryl;heteroaryl; aryl-lower alkyl; heteroaryl-lower alkyl;—(CH₂)_(p)(CHR⁶¹)_(s)OR⁶⁵; —(CH₂)_(p)(CHR⁶¹)_(s)SR⁶⁶; or—(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;—(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; R⁶⁵ is H; lower alkyl; loweralkenyl; aryl, aryl-lower alkyl; heteroaryl-lower alkyl; —COR⁵⁷;—COOR⁵⁷; or —CONR⁵⁸R⁵⁹; R⁶⁶ is H; lower alkyl; lower alkenyl; aryl;aryl-lower alkyl; heteroaryl-lower alkyl; or —CONR⁵⁸R⁵⁹; m is 2-4; o is0-4; p is 1-4; q is 0-2; r is 1 or 2; s is 0 or 1; Z is a chain of nα-amino acid residues, n being the integer 12 and the positions of saidamino acid residues in said chain being counted starting from theN-terminal amino acid, whereby these amino acid residues are, dependingon their position in the chains, Gly, NMeGly, Pro or Pip, or of formula-A-CO—, or of formula —B—CO—, or of one of the types C: —NR²⁰CH(R⁷²)CO—;D: —NR²⁰CH(R⁷³)CO—; E: —NR²⁰CH(R⁷⁴)CO—; F: —NR²⁰CH(R⁸⁴)CO—; and H:—NR²⁰—CH(CO—)—(CH₂)₄₋₇—CH(CO—)—NR²⁰—;—NR²⁰—CH(CO—)—(CH₂)_(p)SS(CH₂)_(p)—CH(CO—)—NR²⁰—;—NR²⁰—CH(CO—)-(—(CH₂)_(p)NR²⁰CO(CH₂)_(p)—CH(CO—)—NR²⁰—; and—NR²⁰—CH(CO—)-(—(CH₂)_(p)NR²⁰CONR²⁰(CH₂)_(p)—CH(CO—)—NR²⁰—; I:—NR⁸⁶CH₂CO—; R⁷¹ is lower alkyl; lower alkenyl;—(CH₂)_(p)(CHR⁶¹)_(s)OR⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)SR⁷⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p) (CHR⁶¹)_(s) OCONR³³R⁷⁵;—(CH₂)_(p) (CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁷⁵;—(CH₂)_(p)CONR⁵⁸R⁵⁹; —(CH₂)_(p)PO(OR⁶²)₂; —(CH₂)_(p)SO₂R⁶²; or—(CH₂)_(o)—C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶; R⁷² is H, lower alkyl; lower alkenyl;—(CH₂)_(p)(CHR⁶¹)_(s)OR⁸⁵; or —(CH₂)_(p)(CHR⁶¹)_(s)SR⁸⁵; R⁷³ is—(CH₂)_(o)R⁷⁷; —(CH₂)_(r)O(CH₂)_(o)R⁷⁷; —(CH₂)_(r)S(CH₂)_(o)R⁷⁷; or—(CH₂)_(s)NR²⁰(CH₂)_(o)R⁷⁷; R⁷⁴ is —(CH₂)_(p)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁷⁷R⁸⁰;—(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;—(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁸⁰C(═NR⁸⁰NR⁷⁸R⁷⁹;—(CH₂)_(p)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰; —(CH₂)_(p)C₆H₄NR⁷⁸R⁷⁹;—(CH₂)_(p)C₆H₄NR⁷⁷R⁸⁰; —(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;—(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)C₆H₄N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰;—(CH₂)_(r)O(CH₂)_(m)NR⁷⁸R⁷⁹; —(CH₂)_(r)O(CH₂)_(m)NR⁷⁷R⁸⁰;—(CH₂)_(r)O(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(m)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(m)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰;—(CH₂)_(r)O(CH₂)_(p)C₆H₄CNR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(m)NR⁷⁸R⁷⁹; —(CH₂)_(r)S(CH₂)_(m)NR⁷⁷R⁸⁰;—(CH₂)_(r)S(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(m)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(m)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰;—(CH₂)_(r)S(CH₂)_(p)C₆H₄CNR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁸⁰COR⁶⁴;—(CH₂)_(p)NR⁸⁰COR⁷⁷; —(CH₂)_(p)NR⁸⁰CONR⁷⁸R⁷⁹;—(CH₂)_(p)C₆H₄NR⁸⁰CONR⁷⁸R⁷⁹; or —(CH₂)_(p)NR²⁰CO—[(CH₂)_(u)—X]_(t)—CH₃where X is —O—; —NR²⁰—, or —S—; u is 1-3, and t is 1-6; R⁷⁵ is loweralkyl; lower alkenyl; or aryl-lower alkyl; R³³ and R⁷⁵ taken togethercan form: —(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; R⁷⁵ and R⁸² taken together can form: —(CH₂)₂₋₆—;—(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; R⁷⁶ is H;lower alkyl; lower alkenyl; aryl-lower alkyl; —(CH₂)_(o)OR⁷²;—(CH₂)_(o)SR⁷²; —(CH₂)_(o)NR³³R³⁴; —(CH₂)_(o)OCONR³³R⁷⁵;—(CH₂)_(o)NR²⁰CONR³³R⁸²; —(CH₂)_(o)COOR⁷⁵; —(CH₂)_(o)CONR⁵⁸R⁵⁹;—(CH₂)_(o)PO(OR⁶⁰)₂; —(CH₂)_(p)SO₂R⁶²; or —(CH₂)_(o)COR⁶⁴; R⁷⁷ is aheteroaryl group of one of the formulae

R⁷⁸ is H; lower alkyl; aryl; or aryl-lower alkyl; R⁷⁸ and R⁸² takentogether can form: —(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷ (CH₂)₂—; R⁷⁹ is H; lower alkyl; aryl; or aryl-lower alkyl;or R⁷⁸ and R⁷⁹, taken together, can be —(CH₂)₂₋₇—; —(CH₂)₂O(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; R⁸⁰ is H; or lower alkyl; R⁸¹ is H; lower alkyl; oraryl-lower alkyl; R⁸² is H; lower alkyl; aryl; heteroaryl; or aryl-loweralkyl; R³³ and R⁸² taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷ (CH₂)₂—; R⁸³ is H; lower alkyl; aryl; or—NR⁷⁸R⁷⁹; R⁸⁴ is —(CH₂)_(m)(CHR₆₁)_(s)OH; —(CH₂)pCOOR₈₀;—(CH₂)_(m)(CHR₆₁)_(s)SH; —(CH₂)_(p)CONR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁸⁰CONR⁷⁸R⁷⁹;—(CH₂)_(p)C₆H₄CONR⁷⁸R⁷⁹; or —(CH₂)_(p)C₆H₄NR⁸⁰CONR⁷⁸R⁷⁹; R⁸⁵ is loweralkyl; or lower alkenyl; R⁸⁶ is R⁷⁴; —(CH₂)_(o)R⁷⁷; —(CH₂)_(o)—CHR³³R⁷⁵;or —[(CH₂)_(u)—X′]_(t)—(CH₂)_(v)NR⁷⁸R⁷⁹; or—[(CH₂)_(u)—X′]_(t)—(CH₂)_(v)—C(═NR⁸⁰)NR⁷⁸R⁷⁹ where X is —O—, —NR²⁰—,—S—; or —OCOO—, u is 1-3, t is 1-6, and v is 1-3; wherein the amino acidresidues in positions 1 to 12 are: P1: of type C or of type D or of typeE or of type F, or the residue is Pro or Pip; P2: of type E, or of typeF or the residue is Gly, NMeGly, Pro or Pip; P3: or of type E, of typeF; P4: of type C, or of type D, or of type F, or the residue is Gly orNMeGly; P5: of type E, or of type D, or of type C, or of type F, or offormula -A-CO— or the residue is Gly, NMeGly, Pro or Pip; P6: of type E,or of type F, or of formula —B—CO—, or the residue is Gly or NMeGly; P7:of type C, or of type E or of type F; P8: of type D, or of type C, orthe residue is Pro or Pip; P9: of type C, or of type D or of type F, orthe residue is Gly or NMeGly; P10: of type D, or of type C, or theresidue is Pro or Pip; P11: of type E or of type F or the residue is Glyor NMeGly; and P12: of type C or of type D or of type E or of type F, orthe residue is Pro or Pip; or P4 and P9 and/or P2 and P11, takentogether, can form a group of type H; at P4, P6, P9 also D-isomers beingpossible; and pharmaceutically acceptable salts thereof.
 2. A compoundaccording to claim 1 wherein

is other than a group of formula (a3); R⁷⁴ is other than—(CH₂)_(p)NR²⁰CO—[(CH₂)_(u)—X]_(t)—CH₃; n is 12; and the amino acidresidues in positions 1 to 12 are: P1: of type C or of type D or of typeE or of type F, or the residue is Pro; P2: of type E, or of type F orthe residue is Gly; P3: or of type E, of type F; P4: of type C, or oftype D, or of type F; P5: of type E, or of type D, or of type C, or oftype F, or the residue is Gly or Pro; P6: of type E, or of type F, or offormula —B—CO—, or the residue is Gly; P7: of type C, or of type E or oftype F; P8: of type D, or of type C, or the residue is Pro; P9: of typeC, or of type D or of type F; P10: of type D, or of type C, or theresidue is Pro; P11: of type E or of type F or the residue is Gly; andP12: of type C or of type D or of type E or of type F, or the residue isPro; or P4 and P9 and/or P2 and P11, taken together, can form a group oftype H; at P6 also D-isomers being possible; and pharmaceuticallyacceptable salts thereof.
 3. A compound according to claim 1 wherein

is a group of formula (a1) or (a2).
 4. A compound according to claim 3wherein A is a group of one of the formulae A1 to A69; R¹ is hydrogen orlower alkyl; R² is H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (whereR⁵⁵ is lower alkyl; or lower alkenyl); —CH₂)_(m)SR⁵⁶ (where R⁵⁶ is loweralkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³ is lower alkyl;or lower alkenyl; R³⁴ is H; or lower alkyl; or R³³ and R³⁴ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H; lower alkyl; or lower alkenyl; R⁷⁵is lower alkyl; or R³³ and R⁷⁵ taken together are —(CH₂)₂₋₆—; —(CH₂)₂—;—(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; orlower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰ is H; or lower alkyl;R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H; or lower alkyl; orR³³ and R⁸² taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl; R⁶⁴ is loweralkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; orlower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl; or loweralkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy); R³ is H; lower alkyl; loweralkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; or lower alkenyl);—(CH₂)_(m)SR⁵⁶ (where R⁵⁶ is lower alkyl; or lower alkenyl);—(CH₂)_(m)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—; —(CH₂)₂—;—(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; orlower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R⁴ is H;lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—; —(CH₂)₂—;—(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; orlower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹taken together are (CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: is H; or lower alkyl);—(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is lower alkyl; or lower alkenyl);—(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alkyl; or lower alkenyl); or—(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; lower alkyl; lower alkenyl;or lower alkoxy); R⁵ is lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵(where R⁵⁵ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶is lower alkyl; or lower alkenyl); (CH₂)_(o)NR³³R³⁴ (where R³³ is loweralkyl; or lower alkenyl; R³⁴ is H; or lower alkyl; or R³³ and R³⁴ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl; or lower alkenyl;R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are —(CH₂)₂₋₆—;—(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ isH; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ is H; or loweralkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H; or loweralkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl; R⁶⁴ is alkyl;alkenyl; aryl; aryl-lower alkyl; or heteroaryl-lower alkyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl; or lower alkenyl; and R⁵⁹is H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ isH; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alkyl; or loweralkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; lower alkyl;lower alkenyl; or lower alkoxy); R⁶ is H; lower alkyl; lower alkenyl;—(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; or lower alkenyl);—(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or lower alkenyl);—(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R⁷ is loweralkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵ is lower alkyl; or loweralkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶ is lower alkyl; or lower alkenyl);—(CH₂)_(q)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(r)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R⁸ is H; F;Cl; CF₃; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is loweralkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; orlower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or loweralkenyl; R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H;or lower alkyl; or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵taken together are —(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ is H; or lower alkyl; R³³ is H; orlower alkyl; or lower alkenyl; R⁸² is H; or lower alkyl; or R³³ and R⁸²taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl; R⁶⁴ is loweralkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; orlower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl; or loweralkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy); R⁹ is lower alkyl; loweralkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; or lower alkenyl);—(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or lower alkenyl);—(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R¹⁰ islower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H is or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R¹¹ is H;lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—; —(CH₂)₂—;—(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; orlower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl; R⁶⁴is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is loweralkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl;or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R¹² is H;lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(r)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R¹³ islower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(r)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R¹⁴ is H;lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl is R⁸²: H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—; —(CH₂)₂—;—(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; orlower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; lower alkyl; R⁶⁴is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is loweralkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl;or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R¹⁵ islower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ isH; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or loweralkyl; or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ is H; or lower alkyl; R³³ is H; orlower alkyl; or lower alkenyl; R⁸² is H; or lower alkyl; or R³³ and R⁸²taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl; R⁶⁴ is loweralkyl; or lower alkenyl); —NR²⁰CO lower alkyl (R²⁰═H; or lower alkyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl, or lower alkenyl; and R⁵⁹is H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alkyl; or lower alkenyl);or (CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy); R¹⁶ is lower alkyl; lower alkenyl;—(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; or lower alkenyl);—(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or lower alkenyl);—(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); and R¹⁷ islower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(r)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).
 5. Acompound according to claim 3 wherein A is a group of one of theformulae A5 (with R² being H); A8; A22; A25; A38 (with R² being H); A42;and A50.
 6. A compound according to claim 5 wherein A is a group offormula

wherein R²⁰ is H or lower alkyl; and R⁶⁴ is alkyl; alkenyl;—[(CH₂)_(u)—X]_(t)—CH₃, wherein X is —O—; —NR²⁰—, —S—; u=1-3, t=1-6,aryl; aryl-lower alkyl; or heteroaryl-lower alkyl.
 7. A compoundaccording to claim 6 wherein R⁶⁴ is n-hexyl; n-heptyl; 4-(phenyl)benzyl;diphenylmethyl, 3-amino-propyl; 5-amino-pentyl; methyl; ethyl;isopropyl; isobutyl; n-propyl; cyclohexyl; cyclohexylmethyl; n-butyl;phenyl; benzyl; (3-indolyl)methyl; 2-(3-indolyl)ethyl; (4-phenyl)phenyl;n-nonyl; CH₃—OCH₂CH₂—OCH₂— or CH₃—(OCH₂CH₂)₂—OCH₂—.
 8. A compoundaccording to claim 3 wherein A is a group of one of the formulae A70 toA104; R²⁰ is H; H or lower alkyl; R¹⁸ is lower alkyl; R¹⁹ is loweralkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵ is lower alkyl; or loweralkenyl); —(CH₂)_(p)SR⁵⁶ (where R⁵⁶ is lower alkyl; or lower alkenyl);—(CH₂)_(p)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷:lower alkyl; or lower alkenyl); (CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(p)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or (CH₂)_(o)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R²¹ is H;lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—; —(CH₂)₂—;—(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; orlower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl, or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R²² islower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl, or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF; lower alkyl; lower alkenyl; or lower alkoxy); R²³ is H;lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —NR²⁰CO lower alkyl (R²⁰═H; orlower alkyl) —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl, or loweralkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy); R²⁴ is lower alkyl; loweralkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; or lower alkenyl);—(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or lower alkenyl);—(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —NR²⁰CO lower alkyl (R²⁰═H; orlower alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl, or loweralkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy); R²⁵ is H; lower alkyl; loweralkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; or lower alkenyl);—(CH₂)_(m)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—; —(CH₂)₂—;—(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷ (CH₂)₂—; where R⁵⁷ is H; orlower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl; orlower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—; —(CH₂)₂—;—(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷ (CH₂)₂—; where R⁵⁷ is H; orlower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R²⁶ is H;lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³ is lower alkyl; or loweralkenyl; R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H;or lower alkyl; or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰ is H; or lower alkyl; R³³ is H; orlower alkyl; or lower alkenyl; R⁸² is H; or lower alkyl; or R³³ and R⁸²taken together are —(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷ (CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl; R⁶⁴ is loweralkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; orlower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl; or loweralkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy); or, alternatively, R²⁵ and R²⁶taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR³⁴(CH₂)₂—; R²⁷ is H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵(where R⁵⁵ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶is lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is loweralkyl; or lower alkenyl; R³⁴ is H; or lower alkyl; or R³³ and R³⁴ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl; or lower alkenyl;R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are —(CH₂)₂₋₆—;—(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ isH; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ is H; or loweralkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H; or loweralkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl; R⁶⁴ is loweralkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; orlower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl, or loweralkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy); R²⁸ is lower alkyl; loweralkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; or lower alkenyl);—(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or lower alkenyl);—(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl, or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); and R²⁹ islower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —NR²⁰CO lower-alkyl (R²⁰═H; orlower alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl, or loweralkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy).
 9. A compound according to claim8 wherein R²³, R²⁴ and R²⁹ are —NR²⁰—CO-lower alkyl where R²⁰ is H; orlower alkyl.
 10. A compound according to claim 8 wherein A is a group ofone of the formulae A74 (with R²² being H); a75; A76; A77 (with R²²being H); A78; and A79.
 11. A compound according to claim 3 wherein B isa group of formula —NR²⁰CH(R⁷¹)— or an enantiomer of one of the groupsA5 (with R² being H); A8; A22; A25; A38 (with R² being H); A42; A47; andA50.
 12. A compound according to claim 11 wherein B—CO is Ala; Arg; Asn;Cys; Gln; Gly; H is; Ile; Leu; Lys; Met; Phe; Pro; Ser; Thr; Trp; Tyr;Val; Cit; Orn; tBuA; Sar; t-BuG; 4AmPhe; 3AmPhe; 2AmPhe; Phe(mC(NH₂)═NH;Phe(pC(NH₂)═NH; Phe(mNHC(NH₂)═NH; Phe(pNHC(NH₂)═NH; Phg; Cha;cyclobutylalanine; cyclopentylalanine; Nle; 2-Nal; 1-Nal; 4Cl-Phe;3Cl-Phe; 2Cl-Phe; 3,4Cl₂Phe; 4F-Phe; 3F-Phe; 2F-Phe; Tic; Thi; Tza; Mso;AcLys; Dpr; A₂Bu; Dbu; Abu; Aha; Aib; Y(Bzl); Bip; S(Bzl); T(Bzl); hCha;hCys; hSer, hArg; hPhe; Bpa; Pip; OctG; MePhe; MeNle; MeAla; MeIle;MeVal; or MeLeu.
 13. A compound according to claim 11 wherein B is agroup, having (L)-configuration, of formula

wherein R²⁰ is H; or lower alkyl; and R⁶⁴ is alkyl; alkenyl;—[(CH₂)_(u)—X]_(t)—CH₃, wherein X is —O—, NR²⁰—, —S—; u=1-3, t=1-6;aryl; aryl-lower alkyl; or heteroaryl-lower alkyl.
 14. A compoundaccording to claim 13 wherein R⁶⁴ is n-hexyl; n-heptyl;4-(phenyl)benzyl; diphenylmethyl, 3-amino-propyl; 5-amino-pentyl;methyl; ethyl; isopropyl; isobutyl; n-propyl; cyclohexyl;cyclohexylmethyl; n-butyl; phenyl; benzyl; (3-indolyl)methyl;2-(3-indolyl)ethyl; (4-phenyl)phenyl; n-nonyl; CH₃—OCH₂CH₂—OCH₂— orCH₃—(OCH₂CH₂)₂—OCH₂—.
 15. A compound according to claim 1 wherein

is a group of formula (b1) or (1); R¹ is H; or lower alkyl; R²⁰ is H; orlower alkyl; R³⁰ is H; or methyl; R³¹ is H; lower alkyl; lower alkenyl;—(CH₂)_(p)OR⁵⁵ (where R⁵⁵ is lower alkyl; or lower alkenyl);—(CH₂)_(p)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷ (CH₂)₂—; where R⁵⁷ isH; or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³ is H; or loweralkyl; or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰ is H; or lower alkyl; R³³ is H; orlower alkyl; or lower alkenyl; R⁸² is H; or lower alkyl; or R³³ and R⁸²taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl; R⁶⁴ is loweralkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; orlower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl, or loweralkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alkyl; orlower alkenyl); or —(CH₂)_(r)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy); most preferably —CH₂CONR⁵⁸R⁵⁹(where R⁵⁸ is H; or lower alkyl; and R⁵⁹ is lower alkyl; or loweralkenyl); R³² is H; or methyl; R³³ is lower alkyl; lower alkenyl;—(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; or lower alkenyl);—(CH₂)_(m)NR³⁴R⁶³ (where R³⁴ is lower alkyl; or lower alkenyl; R⁶³ is H;or lower alkyl; or R³⁴ and R⁶³ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)OCONR⁷⁵R⁸² (where R⁷⁵ is lower alkyl; orlower alkenyl; R⁸² is H; or lower alkyl; or R⁷⁵ and R⁸² taken togetherare —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR⁷⁸R⁸² (where R²⁰ isH; or lower alkyl; R⁷⁸ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R⁷⁸ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); R³⁴ is H; or loweralkyl; R³⁵: is H; lower alkyl; lower alkenyl; (CH₂)_(m)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³ is loweralkyl; or lower alkenyl; R³⁴ is H; or lower alkyl; or R³³ and R³⁴ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl; or lower alkenyl;R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰ is H; or loweralkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H; or loweralkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl; R⁶⁴ is loweralkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; orlower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl; or loweralkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); R³⁶: lower alkyl; lower alkenyl; oraryl-lower alkyl; R³⁷ is H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵(where R⁵⁵ is lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (whereR³³ is lower alkyl; or lower alkenyl; R³⁴ is H; or lower alkyl; or R³³and R³⁴ taken together are —(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷ (CH₂)₂—; where R⁵⁷ is H; or loweralkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl; or loweralkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—; —(CH₂)₂—;—(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; orlower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl, or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alky; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); and R³⁸ isH; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵ is lower alkyl;or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³ is lower alkyl; or loweralkenyl; R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷ (CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³ is H;or lower alkyl; or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵taken together are —(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰ is H; or lower alkyl; R³³ is H; orlower alkyl; or lower alkenyl; R⁸² is H; or lower alkyl; or R³³ and R⁸²taken together are —(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷ (CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl; R⁶⁴ is loweralkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; orlower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl, or loweralkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂₋₆—; —(CH₂)₂—; —(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy).
 16. A compound according toclaim 15 wherein R¹ is H; R²⁰ is H; R³⁰ is H; R³¹ is carboxymethyl; orlower alkoxycarbonylmethyl; R³² is H; R³⁵ is methyl; R³⁶ is methoxy; R³⁷is H and R³⁸ is H.
 17. A compound according to claim 1 wherein n is 12and the α-amino acid residues in positions 1 to 12 in the chain Z are:P1: of type C, or of type D, or of type F, or the residue is Pro or Pip;P2: of type E, or of type F, or the residue is Gly, NMeGly, Pro or Pip;P3: or of type E, of type F; P4: of type C, or of type D, or of type F,or the residue is Gly or NMeGly; P5: of type E, or of type D, or of typeF, or the residue is Gly, NGly, Pro or Pip; P6: of type E, or of type F,or of formula —B—CO—, or the residue is Gly or NMeGly; P7: of type E, orof type F; P8: of type D, or of type C, or the residue is Pro or Pip;P9: of type C, or of type D, or of type F, or the residue is Gly orNMeGly; P10: of type D, or of type C, or the residue is Pro or Pip; P11:of type E, or of type F, or the residue is Gly or NMeGly; and P12: oftype E or of type F, or the residue is Pro or Pip; or P4 and P9, takentogether, form a group of type H; at P4, P6, P9 also D-isomers beingpossible.
 18. A compound according to claim 17 wherein the α-amino acidresidues in positions 1 to 12 of the chain Z are: P1: Tyr; P2: Arg, Gly;P3: Cit; P4: Val, Phe, Gly, Ile, Thr, Gln, Cys; P5: Arg; P6: Arg,^(D)Arg; P7: Arg; P8: Trp, 2-Nal; P9: Val, Phe, Gly, Ile, Thr, Gln, Cys;P10: Tyr; P11: Cit, Gly; and P12: Lys; or Cys at P4 and P9 form adisulfide bridge.
 19. A compound of formula I as defined in claim 1,further including enantiomers of said compound of formula I.
 20. Acompound according to claim 1 having CXCR4 antagonizing activity, whichalso has anticancer activity and/or anti-inflammatory activity, whereinthe cancer is selected from the group consisting of breast cancer, braincancer, prostate cancer, lung cancer, kidney cancer, neuroblastoma,non-hodgkin's lymphoma, ovarian cancer, multiple myeloma, chroniclymphocytic leukemia, pancreatic cancer, melanoma, and whereas theinflammatory activity is selected from the group consisting of asthma,allergic rhinitis, hypersensitivity lung diseases, hypersensitivitypneumonitis, eosinophilic pneumonias, delayed-type hypersensitivity,interstitial lung disease (ILD), idiopathic pulmonary fibrosis, ILDassociated with rheumatoid arthritis, systemic lupus erythematosus,ankylosing sponylitis, systemic sclerosis, Sjogren's syndrome, systemicanaphylaxis or hypersensitivity responses, drug allergies, rheumatoidarthritis, psoriatic arthritis, systemic lupus erythematosus, myastheniagravis, juvenile onset diabetes, glomerulonephritis, autoimmunethyroiditis, graft rejection including allograft rejection orgraft-versus-host disease, inflammatory bowel diseases and inflammatorydermatoses.
 21. A pharmaceutical composition containing a compoundaccording to claim 1 and a pharmaceutically inert carrier.
 22. Acomposition according to claim 21 in a form suitable for oral, topical,transdermal, injection, buccal, transmucosal, pulmonary or inhalationadministration.
 23. A composition according to claim 21 in form oftablets, dragees, capsules, solutions, liquids, gels, plaster, creams,ointments, syrup, slurries, suspensions, spray, nebuliser orsuppositories.
 24. A method of antagonizing CXCR4 in a patient in needthereof, comprising administering to the patient an effective amount ofa compound according to claim
 1. 25. The method according to claim 24wherein said antagonism of CXCR4 is intended to be for slowing viralprogression in infected patients.
 26. A process for the manufacture of acompound according to claim 1 which process comprises (a) coupling anappropriately functionalized solid support with an appropriatelyN-protected derivative of that amino acid which in the end-product is inposition 8, 9 or 10, any functional group which may be present in saidN-protected amino acid derivative being likewise appropriatelyprotected; (b) removing the N-protecting group from the product thusobtained; (c) coupling the product thus obtained with an appropriatelyN-protected derivative of that amino acid which is one position nearerthe N-terminal amino acid residue, any functional group which may bepresent in said N-protected amino acid derivative being likewiseappropriately protected; (d) removing the N-protecting group from theproduct thus obtained; (e) repeating steps (c) and (d) until theN-terminal amino acid residue has been introduced; (f) coupling theproduct thus obtained with a compound of the general formula

is as defined in claim 1 and X is an N-protecting group or,alternatively, if

is to be group (a1) or (a2), above, (fa) coupling the product obtainedin step (e) with an appropriately N-protected derivative of an aminoacid of the general formulaHOOC—B—H  IIIorHOOC-A-H  IV wherein B and A are as defined in claim 1, any functionalgroup which may be present in said N-protected amino acid derivativebeing likewise appropriately protected; (fb) removing the N-protectinggroup from the product thus obtained; and (fc) coupling the product thusobtained with an appropriately N-protected derivative of an amino acidof the above general formula IV and, respectively, III, any functionalgroup which may be present in said N-protected amino acid derivativebeing likewise appropriately protected; and, respectively, if

is to be group (a3), above, (fa′) coupling the product obtained in step(e) with an appropriately N-protected derivative of an amino acid of theabove general formula III, any functional group which may be present insaid N-protected amino acid derivative being likewise appropriatelyprotected; (fb′) removing the N-protecting group from the product thusobtained; and (fc′) coupling the product thus obtained with anappropriately N-protected derivative of an amino acid of the abovegeneral formula III, any functional group which may be present in saidN-protected amino acid derivative being likewise appropriatelyprotected; (g) removing the N-protecting group from the product obtainedin step (f) or (fc) or (fc′); (h) coupling the product thus obtainedwith an appropriately N-protected derivative of that amino acid which isin position 12 if n is 12, any functional group which may be present insaid N-protected amino acid derivative being likewise appropriatelyprotected; (i) removing the N-protecting group from the product thusobtained; (j) coupling the product thus obtained with an appropriatelyN-protected derivative of that amino acid which is one position fartheraway from position 12 if n is 12, any functional group which may bepresent in said N-protected amino acid derivative being likewiseappropriately protected; (k) removing the N-protecting group from theproduct thus obtained; (l) repeating steps (j) and (k) until all aminoacid residues have been introduced; (m) optionally, selectivelydeprotecting one or several protected functional group(s) present in themolecule and appropriately substituting the reactive group(s) thusliberated; (n) optionally, forming one, two or three interstrandlinkage(s) between side-chains of appropriate amino acid residues atopposite positions of the β-strand region; (o) detaching the productthus obtained from the solid support; (p) cyclizing the product cleavedfrom the solid support; (q) removing any protecting groups present onfunctional groups of any members of the chain of amino acid residuesand, optionally, any protecting group(s) which may in addition bepresent in the molecule; and (r) optionally converting the product thusobtained into a pharmaceutically acceptable salt or converting apharmaceutically acceptable, or unacceptable, salt thus obtained intothe corresponding free compound of formula I or into a different,pharmaceutically acceptable, salt.
 27. A process for the manufacture ofa compound according to claim 1 which process comprises (a′) coupling anappropriately functionalized solid support with a compound of thegeneral formula

is as defined above and X is an N-protecting group or, alternatively, if

is to be group (a1) or (a2), above, (a′a) coupling said appropriatelyfunctionalized solid support with an appropriately N-protectedderivative of an amino acid of the general formulaHOOC—B—H  IIIorHOOC-A-H  IV wherein B and A are as defined in claim 1, any functionalgroup which may be present in said N-protected amino acid derivativebeing likewise appropriately protected; (a′b) removing the N-protectinggroup from the product thus obtained; and (a′c) coupling the productthus obtained with an appropriately N-protected derivative of an aminoacid of the above general formula IV and, respectively, III, anyfunctional group which may be present in said N-protected amino acidderivative being likewise appropriately protected; and, respectively, if

is to be group (a3), above, (a′a′) coupling the product obtained in step(e) with an appropriately N-protected derivative of an amino acid of theabove general formula III, any functional group which may be present insaid N-protected amino acid derivative being likewise appropriatelyprotected; (a′b′) removing the N-protecting group from the product thusobtained; and (a′c′) coupling the product thus obtained with anappropriately N-protected derivative of an amino acid of the abovegeneral formula III, any functional group which may be present in saidN-protected amino acid derivative being likewise appropriatelyprotected; (b′) removing the N-protecting group from the productobtained in step (a′), (a′c) or (a′c′); (c′) coupling the product thusobtained with an appropriately N-protected derivative of that amino acidis in position 12 if n is 12, any functional group which may be presentin said N-protected amino acid derivative being likewise appropriatelyprotected; (d′) removing the N-protecting group from the product thusobtained; (e′) coupling the product thus obtained with an appropriatelyN-protected derivative of that amino acid which is one position fartheraway from position 12 if n is 12, any functional group which may bepresent in said N-protected amino acid derivative being likewiseappropriately protected; (f′) removing the N-protecting group from theproduct thus obtained; (g′) repeating steps (e′) and (f′) until allamino acid residues have been introduced; (h′) optionally, selectivelydeprotecting one or several protected functional group(s) present in themolecule and appropriately substituting the reactive group(s) thusliberated; (i′) optionally, forming one, two or three interstrandlinkage(s) between side-chains of appropriate amino acid residues atopposite positions of the β-strand region; (j′) detaching the productthus obtained from the solid support; (k′) cyclizing the product cleavedfrom the solid support; (l′) removing any protecting groups present onfunctional groups of any members of the chain of amino acid residuesand, optionally, any protecting group(s) which may in addition bepresent in the molecule; and (m′) optionally, converting the productthus obtained into a pharmaceutically acceptable salt or converting apharmaceutically acceptable, or unacceptable, salt thus obtained intothe corresponding free compound of formula I or into a different,pharmaceutically acceptable, salt.
 28. A process according to claim 26but wherein N-substituted glycine derivatives are introduced by couplingwith a leaving group-containing acylating agent, followed bynucleophilic displacement with an amine of the formula H₂N—R⁸⁶ which, ifnecessary, is appropriately protected.
 29. A process according to claim28 wherein said leaving group-containing acylating agent is bromo,chloro or iodo acetic acid.
 30. The process according to claim 26wherein the process is modified for the manufacture of enantiomers ofthe compounds in which enantiomers of all chiral starting materials areused.
 31. A process according to claim 27, but wherein an amino acidresidue of type I is introduced by coupling with a leavinggroup-containing acylating agent, followed by nucleophilic displacementwith an amine of the formula H₂N—R⁸⁶ which, if necessary, isappropriately protected.
 32. A process according to claim 27 wherein theprocess is modified for the manufacture of enantiomers of the compoundsin which enantiomers of all chiral starting materials are used.
 33. Aprocess according to claim 28 wherein the process is modified for themanufacture of enantiomers of the compounds in which enantiomers of allchiral starting materials are used.
 34. A process according to claim 29wherein the process is modified for the manufacture of enantiomers ofthe compounds in which enantiomers of all chiral starting materials areused.